TWI686393B - Therapeutic compound for pain and synthesis thereof - Google Patents
Therapeutic compound for pain and synthesis thereof Download PDFInfo
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- TWI686393B TWI686393B TW107117875A TW107117875A TWI686393B TW I686393 B TWI686393 B TW I686393B TW 107117875 A TW107117875 A TW 107117875A TW 107117875 A TW107117875 A TW 107117875A TW I686393 B TWI686393 B TW I686393B
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- 0 CCCN(*)[C@](C1C2)C(*3CC3)N(*)C[C@@]1[C@@]2C#C Chemical compound CCCN(*)[C@](C1C2)C(*3CC3)N(*)C[C@@]1[C@@]2C#C 0.000 description 5
- VOBLQYJOKGKAHT-UHFFFAOYSA-N CC(C)(C)OC(N(C(CC(C1)C2)C3N2C(C(C=C2)N(C)C=C2F)=O)C1C3OC(C1CC1)=O)=O Chemical compound CC(C)(C)OC(N(C(CC(C1)C2)C3N2C(C(C=C2)N(C)C=C2F)=O)C1C3OC(C1CC1)=O)=O VOBLQYJOKGKAHT-UHFFFAOYSA-N 0.000 description 1
- RDKACBCOJYGZFA-UHFFFAOYSA-N CC(C)(C)OC(N(C(CC(C1)C2)C3N2C(COC)=O)C1C3O)=O Chemical compound CC(C)(C)OC(N(C(CC(C1)C2)C3N2C(COC)=O)C1C3O)=O RDKACBCOJYGZFA-UHFFFAOYSA-N 0.000 description 1
- SSKZGNBYGNKXFA-UHFFFAOYSA-N CC(C)(C)OC(N(C(CC(C1)C2)C3N2C(c(cc2)ncc2F)=O)C1C3O)=O Chemical compound CC(C)(C)OC(N(C(CC(C1)C2)C3N2C(c(cc2)ncc2F)=O)C1C3O)=O SSKZGNBYGNKXFA-UHFFFAOYSA-N 0.000 description 1
- FQEBJRNMVULMRK-HWBDBZLXSA-N CCOC(N(C(C1)C2N(Cc3ccccc3)CC1C1)C1[C@@H]2O)=O Chemical compound CCOC(N(C(C1)C2N(Cc3ccccc3)CC1C1)C1[C@@H]2O)=O FQEBJRNMVULMRK-HWBDBZLXSA-N 0.000 description 1
- LBJJIUWOKULMHS-UHFFFAOYSA-N CN(C(C=C1)C(N(CC2CC3NC4C2)C4C3OC(C2CC2)=O)=O)C=C1F Chemical compound CN(C(C=C1)C(N(CC2CC3NC4C2)C4C3OC(C2CC2)=O)=O)C=C1F LBJJIUWOKULMHS-UHFFFAOYSA-N 0.000 description 1
- HWGGIBJFLIMUCL-ALPUWHEMSA-N CN1C(C2)[C@@H](CC3)[C@@H]3C1CC2O Chemical compound CN1C(C2)[C@@H](CC3)[C@@H]3C1CC2O HWGGIBJFLIMUCL-ALPUWHEMSA-N 0.000 description 1
- FKZQKCRRXFRVIC-RHXSKMILSA-N CN1C(C2)[C@@H](CC3)[C@@H]3C1CC2OC([C@H](CO)c1ccccc1)=O Chemical compound CN1C(C2)[C@@H](CC3)[C@@H]3C1CC2OC([C@H](CO)c1ccccc1)=O FKZQKCRRXFRVIC-RHXSKMILSA-N 0.000 description 1
- YFNGBEOGUNGNHP-JKJWBTBISA-N C[C@@H](C1C2)C3NCC2CC3N1C(OC(C)(C)C)=O Chemical compound C[C@@H](C1C2)C3NCC2CC3N1C(OC(C)(C)C)=O YFNGBEOGUNGNHP-JKJWBTBISA-N 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N O=C(C1CC1)Cl Chemical compound O=C(C1CC1)Cl ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- C07D451/06—Oxygen atoms
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- C07D451/06—Oxygen atoms
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Abstract
Description
本專利申請案主張2015年9月4日申請之美國臨時申請案第62/214,727號及2015年9月4日申請之美國臨時申請案第62/214,734號之權益，其中之每一者全文以引用方式併入本文。 This patent application claims the rights of US Provisional Application No. 62/214,727 filed on September 4, 2015 and US Provisional Application No. 62/214,734 filed on September 4, 2015, the full text of each The way of citation is incorporated into this article.
本發明提供新的醫藥上活性化合物，其可用於治療動物、哺乳動物及人之症狀及病症。 The present invention provides new pharmaceutically active compounds that can be used to treat symptoms and conditions in animals, mammals and humans.
具有醫藥活性之新的化合物可用於治療先前不可治療之症狀、用於與習知醫藥化合物可達成者相比更好地治療症狀、及用於治療先前以習知醫藥化合物可治療的症狀，但是彼等現在不再可有效地治療。 New compounds with medicinal activity can be used to treat previously untreated symptoms, to treat symptoms better than those achievable with conventional pharmaceutical compounds, and to treat symptoms previously treatable with conventional pharmaceutical compounds, but They can no longer be effectively treated now.
本發明提供式XXIII化合物：
在一些實施例中，R1、R2及R3基團中之一或多者可選地經一或多個取代基取代。在各種實施例中，可選取代基選自鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, one or more of the R 1 , R 2 and R 3 groups are optionally substituted with one or more substituents. In various embodiments, the optional substituent is selected from halo, =O, =N-CN, =N-OR', =NR', OR', N(R') 2 , SR', SO 2 R' , SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R') 2 , OOCR', COR' and NO 2 ; Where each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 Aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which is optionally selected from one or more of the following Group substitution: halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 heteroacyl, hydroxy, amine and =O; where Two R's can be joined to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O and S.
在具體實施例中，R3係可選地經取代之芳基甲基或可選地經取代之雜芳基甲基。 In specific embodiments, R 3 is optionally substituted arylmethyl or optionally substituted heteroarylmethyl.
在某些實施例中，本發明包括含有式XXIII化合物及/或其衍生物之醫藥組成物。在一個實施例中，本發明包括一種包含式XXIII化合物及/或衍生物與醫藥上可接受之載劑或稀釋劑的醫藥組成物。在另一實施例中，本發明提供一種用於治療患有症狀、疾病或病症之個體(人或動物)的方法，其包含向個體投予有效量之式XXIII化合物或其衍生物。在一個實施例中，係投予該化合物以實現局部遞送至該個體。在另一實施例中，係投予該化合物以實現全身遞送至該個體。在又一實施例中，式XXIII化合物或其衍生物係用作藥物或用於製造藥物。在一些實施例中，該症狀或病症係疼痛。在具體實施例中，該疼痛係神經性疼痛或慢性疼痛。 In certain embodiments, the present invention includes pharmaceutical compositions containing compounds of formula XXIII and/or derivatives thereof. In one embodiment, the invention includes a pharmaceutical composition comprising a compound and/or derivative of formula XXIII and a pharmaceutically acceptable carrier or diluent. In another embodiment, the present invention provides a method for treating an individual (human or animal) suffering from a symptom, disease or condition, which comprises administering to the individual an effective amount of a compound of formula XXIII or a derivative thereof. In one embodiment, the compound is administered to achieve local delivery to the individual. In another embodiment, the compound is administered to achieve systemic delivery to the individual. In yet another embodiment, the compound of formula XXIII or its derivative is used as a medicament or for the manufacture of a medicament. In some embodiments, the symptom or disorder is pain. In specific embodiments, the pain is neuropathic pain or chronic pain.
在某些實施例中，R3係三氟乙醯基。 In certain embodiments, R 3 is trifluoroacetyl.
在某些實施例中，R1係第三丁基二苯基矽基，R2係氫，並且R3係-COOR4，其中R4係選自由烷基及苄基組成之群組。在進一步實施 例中，R4係苄基，在其他實施例中，R4係具有1至8個碳原子之烷基。在更進一步實施例中，R4係乙基。在其他實施例中，R4係第三丁基。 In certain embodiments, R 1 is tertiary butyldiphenylsilyl, R 2 is hydrogen, and R 3 is -COOR 4 , wherein R 4 is selected from the group consisting of alkyl and benzyl. In further embodiments, R 4 is a benzyl group, and in other embodiments, R 4 is an alkyl group having 1 to 8 carbon atoms. In a still further embodiment, R 4 is ethyl. In other embodiments, R 4 is tertiary butyl.
本發明提供式XXIII(A)化合物：
在一些實施例中、R4可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 4 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R2可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯 基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 2 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R3可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 3 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
本發明提供式XXIII(B)化合物：
在一些實施例中、R5可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯 基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 5 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R1可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 1 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R3可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 3 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
本發明提供式XXIII(C)化合物：
在一些實施例中、R4可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 4 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R5可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 5 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R3可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯 基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 3 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
本發明提供式XXIII(D)化合物：
在一些實施例中、R4可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 4 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R5可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯 基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 5 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R6可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 6 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
本發明提供式XXIII(E)化合物：
在一些實施例中、R4可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下 列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 4 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R5可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 5 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
在一些實施例中、R6可選地經一或多個選自下列之取代基取代：鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 6 is optionally substituted with one or more substituents selected from halo, =O, =N-CN, =N-OR', =NR', OR', N( R') 2 SR', SO 2 R', SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R ') 2 , OOCR', COR' and NO 2 ; wherein each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which Optionally substituted with one or more groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 hetero Acyl, hydroxyl, amine, and =O; where two R's can be connected to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O, and S.
本發明提供式I化合物：
一數量之式I化合物可為鏡像異構純的並且完全由式I.a鏡像異構物或式I.b鏡像異構物所組成。或者，它可包含該等鏡像異構物之混合物，該混合物可含有相等量之式I.a鏡像異構物及式I.b鏡像異構物或可以是具有不同量式I.a鏡像異構物或式I.b鏡像異構物中之每一者的混合物。 A number of compounds of formula I can be mirror-isomerically pure and consist entirely of mirror-isomers of formula I.a or mirror-isomers of formula I.b. Alternatively, it may contain a mixture of such mirror isomers, the mixture may contain equal amounts of the formula Ia mirror isomer and the formula Ib mirror isomer or may have different amounts of formula Ia mirror isomer or formula Ib mirror A mixture of each of the isomers.
在某些實施例中，本發明包括含有式I化合物及/或其衍生物之醫藥組成物。在一個實施例中，本發明包括一種包含式I化合物及/或其衍生物及醫藥上可接受之載劑或稀釋劑的醫藥組成物。在另一實施例中，本發明提供一種用於治療患有症狀、疾病或病症之個體(人或動物)的方法，其包含向該個體投予有效量之式I化合物或其衍生物。在一個實施例中，係投予該化合物以實現局部遞送至該個體。在另一實施例中，係 投予該化合物以實現全身遞送至該個體。在又一實施例中，式I化合物及/或其衍生物係用作藥物或用於製造藥物。在一些實施例中，該症狀或病症係疼痛。在具體實施例中，該疼痛係神經性疼痛或慢性疼痛。 In certain embodiments, the present invention includes pharmaceutical compositions containing compounds of Formula I and/or derivatives thereof. In one embodiment, the invention includes a pharmaceutical composition comprising a compound of formula I and/or its derivatives and a pharmaceutically acceptable carrier or diluent. In another embodiment, the present invention provides a method for treating an individual (human or animal) suffering from a symptom, disease or condition, which comprises administering to the individual an effective amount of a compound of formula I or a derivative thereof. In one embodiment, the compound is administered to achieve local delivery to the individual. In another embodiment, the compound is administered to achieve systemic delivery to the individual. In yet another embodiment, the compound of formula I and/or its derivatives are used as medicaments or in the manufacture of medicaments. In some embodiments, the symptom or disorder is pain. In specific embodiments, the pain is neuropathic pain or chronic pain.
本發明亦提供藉由掌性分離式I化合物之外消旋混合物來製造式I.a或式I.b化合物的方法。 The present invention also provides a method for producing a compound of formula I.a or formula I.b by palmily separating a racemic mixture of a compound of formula I.
在其他實施例中，該方法包括製造式I化合物。在一個此類實施例中，製造該式I化合物之該方法包括使式II化合物：
在其他實施例中，該方法包括製造該式II化合物。在一個此類實施例中，製造該式II化合物之該方法包括使式III化合物：
在其他實施例中，該方法亦包括製造該式III化合物。在一個此類實施例中，製造式該III化合物之該方法包括使式IV化合物：
在其他實施例中，該方法亦包括製造該式IV化合物。在一個此類實施例中，製造該式IV化合物之該方法包括使式V化合物：
在其他實施例中，該方法亦包括製造該式V化合物。在一個此類實施例中，製造該式V化合物之該方法包括將式VI化合物：
在其他實施例中，該方法亦包括製造該式VI化合物。在一個此類實施例中，製造該式VI化合物之該方法包括使式VI.a化合物：
在其他實施例中，該方法亦包括製造該式VI.a化合物。在一個此類實施例中，製造式該VI.a化合物之該方法包括使式VII化合物：
在其他實施例中，該方法亦包括製造該式VII化合物。在一個此類實施例中，製造該式VII化合物之該方法包括使式VIII化合物：
在其他實施例中，該方法亦包括製造該式VIII化合物。在一個此類實施例中，製造該式VIII化合物之該方法包括使式IX化合物：
在其他實施例中，該方法亦包括製造式IX化合物。在一個此類實施例中，製造該式IX化合物之該方法包括使式X化合物：
在其他實施例中，該方法亦包括製造該式X化合物。在一個此類實施例中，製造該式X化合物之該方法包括使式XI化合物：
在其他實施例中，該方法亦包括製造式該XI化合物。在一個此類實施例中，製造該式XI化合物之該方法包括在活化劑存在下使式XII化合物：
在其他實施例中，該方法亦包括製造該式XII化合物。在一個此類實施例中，製造該式XII化合物之該方法包括使式XIII化合物：
在又一實施例中，本發明提供一種式XVIII化合物：
在某些實施例中，本發明包括一種含有式XVIII化合物及/或其衍生物之醫藥組成物。在一個實施例中，本發明包括一種包含式XVIII化合物及醫藥上可接受之載劑或稀釋劑的醫藥組成物。在另一實施例中，本發明提供一種用於治療患有症狀、疾病或病症之個體(人或動物)的方法，其包含向該個體投予有效量之式XVIII化合物。在一個實施例中，係投予該化合物以實現局部遞送至該個體。在另一實施例中，係投予該化合物以實現全身遞送至該個體。在又一實施例中，式XVIII化合物係用作藥物或用於製造藥物。在一些實施例中，該症狀或病症係疼痛，包括但不限於神經性疼痛及慢性疼痛。 In certain embodiments, the present invention includes a pharmaceutical composition containing a compound of formula XVIII and/or its derivatives. In one embodiment, the invention includes a pharmaceutical composition comprising a compound of formula XVIII and a pharmaceutically acceptable carrier or diluent. In another embodiment, the present invention provides a method for treating an individual (human or animal) suffering from a symptom, disease or condition, which comprises administering to the individual an effective amount of a compound of formula XVIII. In one embodiment, the compound is administered to achieve local delivery to the individual. In another embodiment, the compound is administered to achieve systemic delivery to the individual. In yet another embodiment, the compound of formula XVIII is used as a medicament or for the manufacture of a medicament. In some embodiments, the symptom or condition is pain, including but not limited to neuropathic pain and chronic pain.
本發明之一實施例提供一種製造式XVIII化合物之方法，其包括使式XVII化合物：
該方法亦可包括製造該式XVII化合物。在一實施例中，製造該式XVII化合物之該方法包括從式XVI化合物移除該Boc基團並且用氫替換：
該方法亦可包括製造該式XVI化合物。在一實施例中，製造式該XVI化合物之該方法包括使式XV化合物：
該方法亦可包括製造該式XV化合物。在一實施例中，製造該式XV化合物之該方法包括將該TBDPS基團從式XIV化合物移除，並且將其用氫替換：
該方法亦可包括製造該式XIV化合物。在一實施例中，製造該式XIV化合物之該方法包括使式I.a化合物與5-氟吡啶甲酸反應。在一較佳實施例中，該反應進一步包含六氟磷酸1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化物(HATU)及N,N-二異丙基乙胺(DIPEA)。 The method may also include manufacturing the compound of formula XIV. In one embodiment, the method of making the compound of formula XIV includes reacting the compound of formula Ia with 5-fluoropicolinic acid. In a preferred embodiment, the reaction further comprises hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine Onium 3-oxide (HATU) and N,N -diisopropylethylamine (DIPEA).
在又一實施例中，本發明提供一種式XXII化合物：
在某些實施例中，本發明包括一種含有式XXII化合物及/或其衍生物之醫藥組成物。在一個實施例中，本發明包括一種包含式XXII化合物及醫藥上可接受之載劑或稀釋劑的醫藥組成物。在另一實施例中，本發明提供一種用於治療患有症狀、疾病或病症之個體(人或動物)的方法，其包含向該個體投予有效量之式XXII化合物。在一個實施例中，係 投予該化合物以實現局部遞送至該個體。在另一實施例中，係投予該化合物以實現全身遞送至該個體。在又一實施例中，式XXII化合物係用作藥物或用於製造藥物。在一些實施例中，該症狀或病症係疼痛。在具體實施例中，該疼痛係神經性疼痛或慢性疼痛。 In certain embodiments, the present invention includes a pharmaceutical composition containing a compound of formula XXII and/or its derivatives. In one embodiment, the invention includes a pharmaceutical composition comprising a compound of formula XXII and a pharmaceutically acceptable carrier or diluent. In another embodiment, the present invention provides a method for treating an individual (human or animal) suffering from a symptom, disease or disorder, which comprises administering to the individual an effective amount of a compound of formula XXII. In one embodiment, the compound is administered to achieve local delivery to the individual. In another embodiment, the compound is administered to achieve systemic delivery to the individual. In yet another embodiment, the compound of formula XXII is used as a medicament or for the manufacture of a medicament. In some embodiments, the symptom or disorder is pain. In specific embodiments, the pain is neuropathic pain or chronic pain.
本發明之依實施例提供一種製造式XXII化合物之方法，其包括使式XXI化合物：
該方法亦可包括製造該式XXI化合物。在一實施例中，製造該式XXI化合物之該方法包括將該Boc基團從式XX化合物移除，並且將其用氫替換：
該方法亦可包括製造該式XX化合物。在一實施例中，製造該式XX化合物之該方法包括將該TBDPS基團從式XIX化合物移除，並且將其用氫替換：
該方法亦可包括製造該式XIX化合物。在一實施例中，製造該式XIX化合物之該方法包括使式I.b化合物與2-甲氧基乙酸反應。該反應可進一步藉由HATU及DIPEA來執行。 The method may also include manufacturing the compound of formula XIX. In one embodiment, the method of making the compound of formula XIX includes reacting the compound of formula I.b with 2-methoxyacetic acid. This reaction can be further performed by HATU and DIPEA.
前述發明內容以及下列實施方式在結合附圖閱讀時可更好地理解。為了說明本發明之目的，該等圖式顯示本發明的實施例。然而，應理解的是，本發明並不受限於所示的確切配置、實例及手段。 The foregoing summary of the invention and the following embodiments can be better understood when read in conjunction with the drawings. For the purpose of illustrating the invention, the figures show embodiments of the invention. However, it should be understood that the invention is not limited to the precise configurations, examples and instrumentalities shown.
圖1顯示式XII化合物之1HNMR分析之結果。 Figure 1 shows the results of 1H NMR analysis of the compound of formula XII.
圖2顯示式XI化合物之MS分析之結果。 Figure 2 shows the results of MS analysis of the compound of formula XI.
圖3A及3B顯示式X化合物之結構分析之結果。圖3A顯示式X化合物之1HNMR分析之結果。圖3B顯示式X化合物之MS分析之結果。 3A and 3B show the results of structural analysis of the compound of formula X. Figure 3A shows the results of 1H NMR analysis of the compound of formula X. Figure 3B shows the results of MS analysis of the compound of formula X.
圖4顯示式IX化合物之1HNMR分析之結果。 Figure 4 shows the results of 1H NMR analysis of the compound of formula IX.
圖5顯示式VIII化合物之1HNMR分析之結果。 Figure 5 shows the results of 1H NMR analysis of the compound of formula VIII.
圖6顯示式VII化合物之1HNMR分析之結果。 Figure 6 shows the results of 1H NMR analysis of the compound of formula VII.
圖7顯示式VI化合物之1HNMR分析之結果。 Figure 7 shows the results of 1H NMR analysis of the compound of formula VI.
圖8A及8B顯示式V化合物之結構分析之結果。圖8A顯示式V化合物之MS分析之結果。圖8B顯示出式V化合物之1HNMR分析之結果。 8A and 8B show the results of structural analysis of the compound of formula V. Figure 8A shows the results of MS analysis of the compound of formula V. Figure 8B shows the results of 1H NMR analysis of the compound of formula V.
圖9A及9B顯示式IV化合物之結構分析之結果。圖9A顯示式IV化合物之LCMS分析之結果。圖9B顯示式IV化合物之1HNMR分析之結果。 9A and 9B show the results of structural analysis of the compound of formula IV. Figure 9A shows the results of LCMS analysis of the compound of formula IV. 9B shows the results of 1H NMR analysis of the compound of formula IV.
圖10顯示式III化合物之LCMS分析之結果。 Figure 10 shows the results of LCMS analysis of the compound of formula III.
圖11A及11B顯示式II化合物之結構分析之結果。圖11A顯示式II化合物之1HNMR分析之結果。圖11B顯示式II化合物之LCMS分析之結果。 11A and 11B show the results of structural analysis of the compound of formula II. FIG. 11A shows the results of 1H NMR analysis of the compound of formula II. Figure 11B shows the results of LCMS analysis of the compound of formula II.
圖12A及12B顯示式I化合物之結構分析之結果。圖12A顯示式I化合物之LCMS分析之結果。圖12B顯示式I化合物之1HNMR分析之結果。 12A and 12B show the results of structural analysis of the compound of formula I. Figure 12A shows the results of LCMS analysis of the compound of formula I. Figure 12B shows the results of 1H NMR analysis of the compound of formula I.
圖13顯示式XIV化合物之LCMS分析之結果。 Figure 13 shows the results of LCMS analysis of the compound of formula XIV.
圖14顯示式XV化合物之LCMS分析之結果。 Figure 14 shows the results of LCMS analysis of the compound of formula XV.
圖15顯示式XVI化合物之LCMS分析之結果。 Figure 15 shows the results of LCMS analysis of the compound of formula XVI.
圖16顯示式XVII化合物之LCMS分析之結果。 Figure 16 shows the results of LCMS analysis of the compound of formula XVII.
圖17A及17B顯示式XVIII化合物之結構分析之結果。圖17A顯示式XVIII化合物之LCMS分析之結果。圖17B顯示式XVIII化合物之1HNMR分析之結果。 17A and 17B show the results of structural analysis of the compound of formula XVIII. Figure 17A shows the results of LCMS analysis of the compound of formula XVIII. Figure 17B shows the results of 1H NMR analysis of the compound of formula XVIII.
圖18顯示式XIX化合物之LCMS分析之結果。 Figure 18 shows the results of LCMS analysis of the compound of formula XIX.
圖19顯示式XX化合物之LCMS分析之結果。 Figure 19 shows the results of LCMS analysis of the compound of formula XX.
圖20顯示式XXI化合物之LCMS分析之結果。 Figure 20 shows the results of LCMS analysis of the compound of formula XXI.
圖21A及21B顯示式XXII化合物之結構分析之結果。圖21A顯示式XXII化合物之LCMS分析之結果。圖21B顯示式XXII化合物之1HNMR分析之結果。 21A and 21B show the results of structural analysis of the compound of formula XXII. Figure 21A shows the results of LCMS analysis of the compound of formula XXII. FIG. 21B shows the results of 1H NMR analysis of the compound of formula XXII.
本發明之實施例在以下詳細地論述。在說明此等實施例中，為了清楚起見，採用特定用語。不過，本發明不意欲被限制於所選擇 的特定用語。在相關技術領域中具有通常知識者將理解可在不脫離本發明之精神及範疇的情況下，採用其他均等組件且開發其他方法。 Embodiments of the present invention are discussed in detail below. In describing these embodiments, specific terms are used for clarity. However, the invention is not intended to be limited to the specific language selected. Those with ordinary knowledge in the relevant technical field will understand that other equal components and other methods can be developed without departing from the spirit and scope of the present invention.
如本文使用，C1-Cx包括C1-C2、C1-C3...C1-Cx。僅為舉例說明，指定為「C1-C4」之基團指示在此部分中有一個至四個碳原子，即含有1個碳原子、2個碳原子、3個碳原子或4個碳原子之基團。因此，僅為舉例說明，「C1-C4烷基」指示在烷基中有一個至四個碳原子，即，烷基係選自甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基及第三丁基之中。 As used herein, C 1 -C x includes C 1 -C 2 , C 1 -C 3 ...C 1 -C x . For illustration only, the group designated as "C 1 -C 4 "indicates that there are one to four carbon atoms in this part, that is, containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbons Atom group. Therefore, for illustration purposes only, "C 1 -C 4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n- Among butyl, isobutyl, second butyl and third butyl.
「烷基」係指脂族烴基團。烷基係支鏈或直鏈。在一些實施例中，「烷基」具有1至10個碳原子，即C1-C10烷基。每當在本文中出現時，數值範圍諸如「1至10」係指給定範圍中之每個整數；例如，「1至10個碳原子」意指烷基由1個碳原子、2個碳原子、3個碳原子、等、直至並且包括10個碳原子所組成，雖然本定義亦涵蓋未指定數值範圍之用語「烷基」之出現。在一些實施例中，烷基係C1-C6烷基。在一個態樣中，烷基係甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。典型烷基包括但是決不限於甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、新戊基或己基。 "Alkyl" means an aliphatic hydrocarbon group. The alkyl group is branched or linear. In some embodiments, "alkyl" having 1 to 10 carbon atoms, i.e. C 1 -C 10 alkyl. Whenever it appears in this text, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom and 2 carbon atoms Atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also covers the appearance of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1 -C 6 alkyl. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl, or third butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, neopentyl, or hexyl.
「伸烷基」係指二價烷基自由基。上述一價烷基之任一者可為藉由從烷基中抽掉第二個氫原子之伸烷基。在一些實施例中，伸烷基係C1-C6伸烷基。在其他實施例中，伸烷基係C1-C4伸烷基。典型伸烷基包括但不限於-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-及類似物。 "Alkyl extension" means a divalent alkyl radical. Any one of the above-mentioned monovalent alkyl groups may be an alkylene group by drawing a second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is a C 1 -C 6 alkylene group. In other embodiments, the alkylene group is a C 1 -C 4 alkylene group. Typical alkylene groups include but are not limited to -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -and the like.
用語「鹵素(halogen)」表示氯、氟、溴或碘。用語「鹵基(halo)」表示氯基、氟基、溴基或碘基。 The term "halogen" means chlorine, fluorine, bromine or iodine. The term "halo" means chloro, fluoro, bromo or iodo.
用語「鹵烷基(haloalkyl)」係指在鏈中具有1至12個碳原子且至少一個氫被鹵素取代的直鏈或支鏈烷基。在一些實施例中，鹵烷基係C1-C6鹵烷基。在一些實施例中，鹵烷基係C1-C4鹵烷基。一例示性的取代基係氟基。本發明之較佳的經取代烷基包括三鹵化烷基，例如三氟甲 基。鹵烷基包括且不限於CF3、CH2F、-CHF2、-CH2Cl、-CH2-CF3及類似物。 The term "haloalkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms in the chain and at least one hydrogen replaced by halogen. In some embodiments, the haloalkyl group is a C 1 -C 6 haloalkyl group. In some embodiments, the haloalkyl group is a C 1 -C 4 haloalkyl group. An exemplary substituent is a fluorine group. Preferred substituted alkyl groups of the present invention include trihalogenated alkyl groups, such as trifluoromethyl. Haloalkyl include, without
用語「烷氧基(alkoxy)」包括具有末端氧之直鏈或支鏈烷基，該末端氧連接該烷基至分子的其餘部分。在一些實施例中，烷氧基係C1-C6烷氧基。在一些實施例中，烷氧基係C1-C4烷氧基。烷氧基包括甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、三級丁氧基、戊氧基等等。 The term "alkoxy" includes linear or branched alkyl groups with terminal oxygen, which connects the alkyl group to the rest of the molecule. In some embodiments, the alkoxy group is a C 1 -C 6 alkoxy group. In some embodiments, the alkoxy group is a C 1 -C 4 alkoxy group. The alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentoxy and the like.
用語「雜環(heterocycle)」表示可選地含有選自O、S及N之雜原子之單或二環烴環結構。雜環基環可在環中具有2至10個碳原子。 The term "heterocycle" means a mono- or bicyclic hydrocarbon ring structure optionally containing heteroatoms selected from O, S and N. The heterocyclyl ring may have 2 to 10 carbon atoms in the ring.
「氮雜環(Azacyclic)」或「氮雜環(azacyclic ring)」係指含有至少一個氮原子的飽和、部分不飽和或芳族之3至7員單環環或8至12員稠合雙環環系統。此等氮雜環可以可選地含有自1至2個選自N、O及S之額外雜原子作為環成員，並且可以可選地經取代到使此等取代具有化學意義之程度。 "Azacyclic" or "azacyclic ring" means a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic ring or 8 to 12 membered fused bicyclic ring containing at least one nitrogen atom Ring system. These nitrogen heterocycles may optionally contain from 1 to 2 additional heteroatoms selected from N, O, and S as ring members, and may be optionally substituted to the extent that such substitutions are chemically meaningful.
用語「芳族(aromatic)」係指具有含有4n+2個π電子之離域π-電子系統的平面環，其中n係整數。用語「芳族」包括碳環芳基(「芳基(aryl)」，例如，苯基)及雜環芳基(或「雜芳基(heteroaryl)」或「雜芳族(heteroaromatic)」)(例如，吡啶)。該用語包括單環或稠合環多環(即，共用相鄰對碳原子之環)基團。 The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes carbocyclic aryl ("aryl", for example, phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") ( For example, pyridine). The term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
用語「碳環(carbocyclic)」或「碳環(carbocyclic)」係指其中形成環骨架之原子都是碳原子的環或環系統。因此，該用語將碳環與其中環骨架含有至少一個不同於碳之原子的「雜環(heterocyclic)」或「雜環(heterocycle)」區分開。在一些實施例中，雙環碳環之兩個環中之至少一者係芳族。在一些實施例中，雙環碳環之環二者都係芳族。 The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which the atoms forming the ring skeleton are all carbon atoms. Therefore, this term distinguishes a carbocycle from a "heterocyclic" or "heterocycle" in which the ring skeleton contains at least one atom other than carbon. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic.
如本文使用，用語「芳基」係指其中形成環之原子中之每一者係碳原子的芳族環。在一個態樣中，芳基係苯基或萘基。在一些實施例中，芳基係苯基。在一些實施例中，芳基係C6-C10芳基。取決於結構，芳基係單自由基或雙自由基(即伸芳基)。 As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, the aryl group is C 6 -C 10 aryl. Depending on the structure, aryl groups are monoradicals or diradicals (ie aryl radicals).
用語「環烷基(cycloalkyl)」係指單環或多環脂族、非芳族自由基，其中形成環之原子(即骨架原子)中之每一者係碳原子。在一些實施例中，環烷基係螺環或橋接化合物。在一些實施例中，環烷基可選地與芳族環稠合，並且連接點在並非芳族環碳原子之碳處。環烷基包括具有3至10個環原子之基團。在一些實施例中，環烷基選自環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環辛基、螺[2.2]戊基、降莰基及雙環[1.1.1]戊基之中。在一些實施例中，環烷基係C3-C6環烷基。 The term "cycloalkyl" refers to monocyclic or polycyclic aliphatic, non-aromatic free radicals, in which each of the atoms forming the ring (ie, skeleton atoms) is a carbon atom. In some embodiments, the cycloalkyl group is a spiro ring or bridge compound. In some embodiments, the cycloalkyl group is optionally fused to an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl includes groups having 3 to 10 ring atoms. In some embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl , Among camphor and bicyclic [1.1.1] pentyl. In some embodiments, the cycloalkyl group is C 3 -C 6 cycloalkyl.
用語「雜烷基(heteroalkyl)」係指烷基之一或多個骨架原子選自除了碳以外之原子，例如，氧、氮(例如-NH-、-N(烷基)-、硫或其組合的烷基。雜烷基係在雜烷基之碳原子處附接至分子之其餘部分。在一個態樣中，雜烷基係C1-C6雜烷基。 The term "heteroalkyl" means that one or more of the backbone atoms of the alkyl group are selected from atoms other than carbon, for example, oxygen, nitrogen (eg -NH-, -N(alkyl)-, sulfur or Combined alkyl. Heteroalkyl is attached to the rest of the molecule at the carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C 1 -C 6 heteroalkyl.
用語「雜環(heterocycle)」或「雜環(heterocyclic)」係指在環(等)中含有一個至四個雜原子的雜芳族環(亦稱為雜芳基)及雜環烷基環(亦稱為雜脂族環基團)，其中環(等)中之每個雜原子選自O、S及N，其中每個雜環基團在其環系統中具有3至10個原子，並且其限制條件係任何環不含有兩個相鄰O或S原子。非芳族雜環基團(亦稱為雜環烷基)包括在其環系統中具有3至10個原子之環並且芳族雜環基團包括在其環系統中具有5至10個原子之環。雜環基團包括苯并稠環系統。非芳族雜環基團之實例係吡咯啶基、四氫呋喃基、二氫呋喃基、四氫噻吩基、
用語「雜芳基」或，替代地，「雜芳族」係指包括一或多個選自氮、氧及硫之環雜原子的芳基。雜芳基之例示性實例包括單環雜芳基及雙環雜芳基。單環雜芳基包括吡啶基、咪唑基、嘧啶基、吡唑基、***基、吡
「雜環烷基(heterocycloalkyl)」或「雜脂環(heteroalicyclic)」基團係指包括至少一個選自氮、氧及硫之雜原子的環烷基。在一些實施例中，雜環烷基與芳基或雜芳基稠合。在一些實施例中，雜環烷基係
波浪線「
「苄基」與-CH2-苯基可互換使用。 "Benzyl" and -CH 2 -phenyl are used interchangeably.
用語「醯基(acyl)」在本文中如有機化學領域習知者般使用。例如，「醯基」可指示具有鍵結烷基之羰基。 The term "acyl" is used in this article as is familiar to those in the field of organic chemistry. For example, "acyl" may indicate a carbonyl group having a bonded alkyl group.
用語「酯(ester)」在本文中如有機化學領域習知者般使用。例如，用語「酯」可指示具有鍵結氧及烷基之羰基或具有鍵結羰基及烷基之氧。 The term "ester" is used herein as is familiar to those in the field of organic chemistry. For example, the term "ester" may indicate a carbonyl group having bonded oxygen and alkyl groups or an oxygen group having bonded carbonyl groups and alkyl groups.
用語「矽基(silyl)」在本文中如有機化學領域習知者般使用。例如，用語「矽基」可指示可對其鍵結氫及/或烷基之矽原子。 The term "silyl (silyl)" is used in this article as is familiar to those in the field of organic chemistry. For example, the term "silyl" may indicate a silicon atom to which hydrogen and/or alkyl groups can be bonded.
如本文使用，用語「Boc-保護(Boc-protection)」表示使用作為保護基之三級丁氧羰基(Boc)之化合物的官能化。此允許化合物總體上能以不然將非所欲地攻擊未被保護基團之試劑處理。然後，被保護基團可去保護以產出所欲原始基團。 As used herein, the term "Boc-protection" means the functionalization of a compound using a tertiary butoxycarbonyl (Boc) compound as a protecting group. This allows the compound to be able to treat reagents that otherwise undesirably attack unprotected groups. The protected group can then be deprotected to produce the desired original group.
用語「醫藥上可接受(pharmaceutically acceptable)」係指經美國聯邦或州政府主管機關或美國以外國家的對應機關核准或可核准者， 或為列在美國藥典(U.S.Pharmacopoeia)或其他一般公認藥典中用於動物(特別是人類)中者。 The term "pharmaceutically acceptable" refers to those approved or approvable by the competent authority of the federal or state government of the United States or the corresponding authority outside the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia Used in animals (especially humans).
「醫藥上可接受之鹽」係指本發明之化合物的鹽，其為醫藥上可接受者並且具有母化合物所欲的藥理活性。具體而言，所述鹽類是無毒的，並可為無機或有機的酸加成鹽和鹼加成鹽。具體而言，此等鹽包括：(1)酸加成鹽，其藉由無機酸來形成，該等無機酸諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及類似物；或以有機酸所形成，例如乙酸、丙酸、己酸、環戊基丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、蘋果酸、馬來酸、延胡索酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥苯甲醯基)苯甲酸、肉桂酸、苦杏仁酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羥乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、4-甲基雙環[2.2.2]-辛-2-烯-1-羧酸、葡萄庚酸、3-苯基丙酸、三甲基乙酸、第三丁基乙酸、月桂基硫酸、葡萄糖酸、麩胺酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸及其類似物；或(2)當母化合物中的酸性質子經金屬離子置換時所形成的鹽，例如鹼金屬離子、鹼土離子或鋁離子；或該酸性質子與有機鹼配位所形成的鹽，例如乙醇胺、二乙醇胺、三乙醇胺、N-甲基葡糖胺及其類似物。僅用於舉例說明，鹽類可進一步包含鈉、鉀、鈣、鎂、銨、四烷基銨及其類似物；且當化合物含有鹼性官能性時，無毒的有機或無機酸的鹽，例如鹽酸鹽、氫溴酸鹽、酒石酸鹽、甲磺酸鹽、乙酸鹽、馬來酸鹽、草酸鹽及類似物。 "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, the salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or by organic acids Formed, for example, acetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzyl) benzoic acid, cinnamic acid, amygdalic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, grape heptanoic acid, 3 -Phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or ( 2) Salts formed when the acid protons in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or salts formed by the coordination of the acid protons and organic bases, such as ethanolamine, diamine Ethanolamine, triethanolamine, N-methylglucamine and the like. For illustrative purposes only, salts may further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains basic functionality, non-toxic salts of organic or inorganic acids, such as Hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate and the like.
「醫藥上可接受的媒劑(pharmaceutically acceptable vehicle)」係指與本發明之化合物一起投予的稀釋劑、佐劑、賦形劑或載劑。「醫藥上可接受的賦形劑(pharmaceutically acceptable excipient)」是指無毒、具生物可耐受性、及不然生物上適合用於投予至個體的物質，例如惰性物質，其被加入至藥用組成物中或者作為媒劑、載劑或稀釋劑以幫助藥劑的投予並與其相容。賦形劑之實例包括碳酸鈣、磷酸鈣、各種糖類及各種類型的澱粉、纖維素衍生物、明膠、植物油及聚乙二醇。 "Pharmaceutically acceptable vehicle" means a diluent, adjuvant, excipient, or carrier administered with the compound of the present invention. "Pharmaceutically acceptable excipient" refers to a substance that is nontoxic, biotolerable, or otherwise biologically suitable for administration to an individual, such as an inert substance, which is added to medicinal use In the composition or as a vehicle, carrier or diluent to aid in the administration and compatibility of the agent. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, and polyethylene glycol.
「個體」包含人。用語「人(human)」、「患者(patient)」和「個體(subject)」在本文中可互換使用。 "Individual" includes people. The terms "human", "patient" and "subject" are used interchangeably in this article.
在一實施例中，「治療(treating或treatment)」任何疾病或病症係指改善該疾病或病症(即阻止或減少疾病或其至少一種臨床症狀的發展)。在另一實施例中，「治療(reating或treatment)」係指改善至少一種身體參數，可能是個體無法辨別之參數。在又另一實施例中，「治療(reating或treatment)」係指調節疾病或病症，不論該疾病或病症是身體上(例如可辨別症狀之穩定)、生理上(例如身體參數的穩定)或兩者之疾病或病症。在又另一實施例中，「治療(treating或treatment)」係指延緩疾病或病症的發生。 In one embodiment, "treating or treating" any disease or condition refers to improving the disease or condition (ie, preventing or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "reating or treatment" refers to improving at least one physical parameter, which may be a parameter that the individual cannot distinguish. In yet another embodiment, "reating or treatment" refers to the regulation of a disease or disorder, whether the disease or disorder is physical (e.g., stabilization of discernable symptoms), physiological (e.g., stabilization of body parameters), or The disease or condition of both. In yet another embodiment, "treating or treatment" refers to delaying the occurrence of a disease or disorder.
在根據本發明之治療方法中，向患有或經診斷有該疾病、病症或症狀之個體投予治療有效量的根據本發明之藥劑。「治療有效量(therapeutically effective amount)」係指一量或劑量，其足以在需要該指定疾病、病症或症狀的治療之患者身上一般性地得到所欲之治療或預防效益。 In the treatment method according to the present invention, a therapeutically effective amount of the agent according to the present invention is administered to an individual suffering from or diagnosed with the disease, disorder or symptom. "Therapeutically effective amount" refers to an amount or dose sufficient to generally obtain the desired therapeutic or preventive benefit in patients who require treatment for the specified disease, disorder or symptom.
本發明之化合物的有效量或劑量可藉由常規方法(例如模型實驗、劑量遞增研究或臨床試驗)，以及藉由考量常規因素(例如投予或藥物遞送的模式或途徑、化合物藥物動力學、疾病、病症或症狀的嚴重程度和病程、個體先前或進行中的療法、個體的健康狀況和對藥物的反應、以及主治醫師的判斷)來確認。劑量實例係介於每天每公斤個體體重自約0.001至約200mg化合物之範圍內，較佳地為約0.05至100mg/kg/天，或約1至35mg/kg/天；為單次劑量單位或分次劑量單位(例如BID、TID、QID)。對於70公斤的人來說，合適劑量之例示範圍係自約0.05至約7g/天，或約0.2至約2.5g/天。 The effective amount or dosage of the compound of the present invention can be determined by conventional methods (such as model experiments, dose escalation studies or clinical trials), and by considering conventional factors (such as the mode or route of administration or drug delivery, compound pharmacokinetics, The severity and course of the disease, disorder or symptom, the individual’s previous or ongoing therapy, the individual’s health status and response to the drug, and the judgment of the attending physician). Examples of dosages range from about 0.001 to about 200 mg of compound per kilogram of body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day; a single dosage unit or Fractional dosage units (eg BID, TID, QID). For a 70 kg person, an exemplary range of suitable dosages is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
「本發明的化合物(Compounds of the present invention)」和均等表述旨在涵蓋本文所述之式之化合物，當上下文允許時，該表述包括醫藥上可接受的鹽及溶劑合物，例如水合物。同樣地，當上下文允許時，提及中間體旨在涵蓋其鹽及溶劑合物，無論彼等是否經請求保護。 "Compounds of the present invention" and equivalent expressions are intended to cover compounds of the formulae described herein. When the context permits, the expression includes pharmaceutically acceptable salts and solvates, such as hydrates. Likewise, when the context permits, references to intermediates are intended to cover their salts and solvates, whether or not they are claimed.
如本文中所使用，用語「同位素變體」係指一種化合物，其在構成此化合物的一或多個原子上包含非天然比例的同位素。例如，化合物的「同位素變體」可以被放射性標記，也就是含有一或多種非放射性或放射性同位素，舉例而言，例如氘(2H或D)、碳13(13C)、氮15(15N)或類似物。可以理解的是，在發生此種同位素取代的化合物中，以下原子若存在時可能會發生改變，因此，舉例來說，任何氫可以是2H/D，任何碳可以是13C，或任何氮可以是15N，而且在本領域的技術範圍內可以測定這類原子的存在及位置。同樣地，本發明可包含具有放射性同位素的同位素變體之製備，例如在所得到的化合物可用於藥物及/或受質組織分布研究的情形中。本發明之放射性標記的化合物可以在診斷方法中使用，例如單光子發射電腦斷層掃描(SPECT)。放射性同位素氚，即3H，及碳-14，即14C由於其容易併入及偵測手段現成而係尤其有用的。此外，可製備經正子發射的同位素(例如11C、18F、15O及13N)取代的化合物，其並可用於正子斷層掃描(PET)研究，以檢查受質受體的佔有情形。 As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more atoms that make up the compound. For example, a "isotopic variant" of a compound can be radioactively labeled, that is, contains one or more non-radioactive or radioactive isotopes, for example, deuterium ( 2 H or D), carbon 13 ( 13 C), nitrogen 15 ( 15 N) or similar. It is understandable that in such isotopically substituted compounds, the following atoms may change if present, so for example, any hydrogen can be 2 H/D, any carbon can be 13 C, or any nitrogen It can be 15 N, and the existence and position of such atoms can be determined within the technical scope of the art. Likewise, the present invention may include the preparation of isotopic variants with radioactive isotopes, for example, in the case where the resulting compound can be used in the study of the distribution of drugs and/or substrate tissues. The radiolabeled compounds of the present invention can be used in diagnostic methods, such as single photon emission computed tomography (SPECT). The radioisotope tritium, ie 3 H, and carbon-14, ie 14 C, are particularly useful due to their ease of incorporation and detection means. In addition, compounds substituted by positron-emitting isotopes (eg, 11 C, 18 F, 15 O, and 13 N) can be prepared, and they can be used in positron tomography (PET) studies to check the occupancy of the acceptor.
本發明之化合物的所有同位素變體，無論其是否具有放射性，均包含在本發明之範疇內。在一個態樣中，本文提供所描述化合物之氘化或氚化類似物。 All isotopic variations of the compounds of the present invention, whether or not they are radioactive, are included within the scope of the present invention. In one aspect, provided herein are deuterated or tritiated analogs of the described compounds.
亦應當理解，具有相同分子式但其原子鍵結的本質或順序或其原子在空間中的排列有所不同的化合物被稱為「異構物(isomer)」。它們的原子在空間中排列不同之異構物稱為「立體異構物(stereoisomer)」。 It should also be understood that compounds that have the same molecular formula but differ in the nature or order of their atomic bonding or the arrangement of their atoms in space are called "isomers." Isomers whose atoms are arranged differently in space are called "stereoisomers".
彼此非為鏡像的立體異構物稱為「非鏡像異構物(diastereomer)」，而彼此為不可重疊鏡像之立體異構物稱為「鏡像異構物(enantiomer)」。當化合物具有不對稱中心時，例如該中心係鍵結到四個不同基團，其可能有一對鏡像異構物。鏡像異構物可藉由其不對稱中心的絕對組態來表徵，其係由Cahn及Prelog的R及S順序法則來描述，或是由分子旋轉偏振光平面的方式來指定為右旋或左旋(即分別為(+)或(-)異構物)。掌性化合物可存在為個別的鏡像異構物或為彼等之混合物。含有相同比例之鏡像異構物的混合物稱為「外消旋混合物(racemic mixture)」。 Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are not mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, the center system is bonded to four different groups, it may have a pair of mirror isomers. The mirror image isomer can be characterized by the absolute configuration of its asymmetric center, which is described by the R and S order rules of Cahn and Prelog, or designated as right-hand or left-hand by the way the molecule rotates the plane of polarized light (Ie, (+) or (-) isomers, respectively). The palmitic compound may exist as individual mirror isomers or as a mixture of them. A mixture containing mirror isomers in the same ratio is called a "racemic mixture".
「互變異構物(Tautomer)」係指具有可互相轉變之特定化合物結構形式的化合物，其差異在於氫原子及電子的轉位。因此，兩個結構可透過π電子及原子(通常為H)的移動而處於平衡狀態。例如，烯醇及酮係互變異構物，因為彼等可藉由酸或鹼之處理而快速地互相轉換。互變異構現象的另一實例係苯基硝基甲烷的酸及硝基形式，同樣藉由酸或鹼之處理形成。 "Tautomer" refers to a compound with a specific compound structure that can be transformed into each other. The difference lies in the transposition of hydrogen atoms and electrons. Therefore, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enol and ketone tautomers, because they can be quickly converted to each other by acid or base treatment. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, also formed by treatment with acids or bases.
互變異構形式可能與達成所欲化合物的最佳化學反應性與生物活性有關。 Tautomeric forms may be related to achieving the best chemical reactivity and biological activity of the desired compound.
如本文使用，用語「濕磨(triturate)」表示純化材料之方法，其中粗製材料用溶劑洗滌。溶劑可選擇，以使得所欲產物不溶解並且雜質可溶解，在此情況下，經純化產物以固體形式保留並且雜質與溶劑一起移除。相反地，溶劑可選擇，以使得所欲產物可溶解並且雜質不溶解，在此情況下，純化產物係呈溶液並且雜質以固體形式移除。然後，溶劑可例如經由蒸發來移除以獲得經純化產物。 As used herein, the term "triturate" refers to a method of purifying materials, where the crude material is washed with a solvent. The solvent can be selected so that the desired product is insoluble and impurities can be dissolved, in which case the purified product remains in solid form and the impurities are removed together with the solvent. Conversely, the solvent can be selected so that the desired product is soluble and the impurities are not dissolved, in which case the purified product is in solution and the impurities are removed in solid form. Then, the solvent can be removed, for example, via evaporation, to obtain a purified product.
本發明之化合物也可存在為「旋轉異構體(rotamer)」，亦即構形異構物，其係於導致不同構形的旋轉受到阻礙時出現，且產生一需要克服才能從一種構形異構物轉換到另一種構形異構物的旋轉能量障壁。 The compounds of the present invention may also exist as "rotamers", that is, configuration isomers, which occur when the rotation of different configurations is hindered and produce a configuration that needs to be overcome The rotation energy barrier of the isomer to another configuration isomer.
本發明之化合物可具有一或多個不對稱中心；因此，此等化合物可以個別(R)-或(S)-立體異構物形式或以其混合物形式來產生。 The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
除非另有說明，本說明書及申請專利範圍中對特定化合物之描述或命名係意欲包括個別的鏡像異構物、及彼等之外消旋混合物或其他混合物。用於判定立體化學及分離立體異構物的方法在本技術領域中為習知。 Unless otherwise stated, the description or nomenclature of specific compounds in this specification and patent application is intended to include individual mirror isomers, and racemic mixtures or other mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are known in the art.
如本文使用，用語「局部遞送(localized delivery)」表示將醫藥或治療劑遞送至身體之特定、有限區域。 As used herein, the term "localized delivery" refers to the delivery of medicine or therapeutic agents to specific, limited areas of the body.
如本文使用，用語「全身遞送(systemic delivery)」表示將醫藥或治療劑遞送至整個身體，例如，經由投予至循環系統。 As used herein, the term "systemic delivery" means the delivery of medicine or therapeutic agents to the entire body, for example, via administration to the circulatory system.
如本文使用，用語「質譜法(mass spectrometry,MS)」表示將化合物離子化以產生帶電分子或分子片段並且量測其等之豐度隨著質量與電荷(m/z)比率而變化(質譜)的分析技術。根據質譜，可得到關於化合物結構之結論。 As used herein, the term "mass spectrometry (MS)" means ionizing a compound to produce charged molecules or molecular fragments and measuring their abundance varies with the mass to charge (m/z) ratio (mass spectrometry) ) Analysis techniques. Based on mass spectrometry, conclusions can be drawn about the structure of the compound.
如本文使用，用語「液相層析-質譜法(liquid chromatography-mass spectrometry,LCMS)」表示將液相層析之物理分離能力與質譜法之分析能力結合的分析技術。在液相層析步驟中，將樣本引入充填有固定相之管柱中，而將樣本之化合物藉由其等在管柱中之滯留時間(Rt)來分離。然後，將與滯留時間間隔相關聯之一或多種化合物引導至質譜儀，以獲得允許得到關於此化合物或此等化合物之結構之結論的質譜。 As used herein, the term "liquid chromatography-mass spectrometry (LCMS)" refers to an analytical technique that combines the physical separation capabilities of liquid chromatography with the analytical capabilities of mass spectrometry. In the liquid chromatography step, the sample is introduced into a column packed with a stationary phase, and the compounds of the sample are separated by their residence time (Rt) in the column. Then, one or more compounds associated with the residence time interval are directed to a mass spectrometer to obtain a mass spectrum that allows conclusions about the structure of the compound or compounds.
如本文使用，用語「薄層層析(thin-layer chromatography,TLC)」表示將樣本中之化合物藉由其等塗佈有固定相材料之板向上吸之不同速率來分離之分析技術。 As used herein, the term "thin-layer chromatography (TLC)" refers to an analytical technique that separates the compounds in a sample by different rates of uptake by a plate coated with a stationary phase material.
如本文使用，用語「核磁共振波譜法(nuclear magnetic resonance spectroscopy,NMR)」表示量測一組原子核對於射頻脈衝之共振回應之強度以允許獲得關於原子核之電子環境之資訊的分析技術。由此，可得出關於原子核駐留之化合物之化學結構的結論。使用氫原子核(質子)之核磁共振波譜技術被稱為質子核磁共振波譜法(1HNMR)。 As used herein, the term "nuclear magnetic resonance spectroscopy (NMR)" refers to an analytical technique that measures the strength of a group of nuclei's resonance response to radio frequency pulses to allow information about the electronic environment of the nuclei to be obtained. From this, conclusions can be drawn about the chemical structure of the compound in which the nucleus resides. The nuclear magnetic resonance spectroscopy technique using hydrogen nuclei (protons) is called proton nuclear magnetic resonance spectroscopy ( 1H NMR).
本發明提供式XXIII化合物：
在一些實施例中，R1可選地經一或多個取代基取代。在各種實施例中，可選取代基選自鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 1 is optionally substituted with one or more substituents. In various embodiments, the optional substituent is selected from halo, =O, =N-CN, =N-OR', =NR', OR', N(R') 2 , SR', SO 2 R' , SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R') 2 , OOCR', COR' and NO 2 ; Where each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 Aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which is optionally selected from one or more of the following Group substitution: halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 heteroacyl, hydroxy, amine and =O; where Two R's can be joined to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O and S.
在一些實施例中，R2可選地經一或多個取代基取代。在各種實施例中，可選取代基選自鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 2 is optionally substituted with one or more substituents. In various embodiments, the optional substituent is selected from halo, =O, =N-CN, =N-OR', =NR', OR', N(R') 2 , SR', SO 2 R' , SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R') 2 , OOCR', COR' and NO 2 ; Where each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 Aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which is optionally selected from one or more of the following Group substitution: halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 heteroacyl, hydroxy, amine and =O; where Two R's can be joined to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O and S.
在一些實施例中，R3可選地經一或多個取代基取代。在各種實施例中，可選取代基選自鹵基、=O、=N-CN、=N-OR'、=NR'、OR'、N(R')2、SR'、SO2R'、SO2NR'2、NR'SO2R'、NR'CONR'2、NR'COOR'、NR'COR'、CN、COOR'、CON(R')2、OOCR'、COR'及NO2；其中每個R'獨立地係H、C1-C6烷基、C2-C6雜烷基、C1-C6醯基、C2-C6雜醯基、C6-C10芳基、C5-C10雜芳基、C7-C12芳基烷基或C6-C12雜芳基烷基，其之每一者可選地經一或多個選自下列之基團取代：鹵基、C1-C4烷基、C1-C4雜烷 基、C1-C6醯基、C1-C6雜醯基、羥基、胺基及=O；其中兩個R'可連接以形成可選地含有至多三個選自N、O及S之雜原子的3至7員環。 In some embodiments, R 3 is optionally substituted with one or more substituents. In various embodiments, the optional substituent is selected from halo, =O, =N-CN, =N-OR', =NR', OR', N(R') 2 , SR', SO 2 R' , SO 2 NR' 2 , NR'SO 2 R', NR'CONR' 2 , NR'COOR', NR'COR', CN, COOR', CON(R') 2 , OOCR', COR' and NO 2 ; Where each R'is independently H, C 1 -C 6 alkyl, C 2 -C 6 heteroalkyl, C 1 -C 6 acetyl, C 2 -C 6 heteroacyl, C 6 -C 10 Aryl, C 5 -C 10 heteroaryl, C 7 -C 12 arylalkyl, or C 6 -C 12 heteroarylalkyl, each of which is optionally selected from one or more of the following Group substitution: halo, C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, C 1 -C 6 acetyl, C 1 -C 6 heteroacyl, hydroxy, amine and =O; where Two R's can be joined to form a 3 to 7 membered ring optionally containing up to three heteroatoms selected from N, O and S.
本發明提供具有式I結構之化合物：
本發明進一步提供式I化合物之治療衍生物，及其合成方法。一種此類衍生物係式XVIII化合物：
式I化合物之第二治療衍生物係式XXII化合物：
本發明化合物係有用於作為藥劑並且可併入醫藥組成物中，該等醫藥組成物包含治療有效量之如本文定義之本發明化合物，及醫藥上可接受之載劑或稀釋劑。 The compounds of the present invention are useful as medicaments and can be incorporated into pharmaceutical compositions containing a therapeutically effective amount of the compounds of the present invention as defined herein, and a pharmaceutically acceptable carrier or diluent.
本發明之化合物亦可使用來製造有用於作為藥劑之衍生物化合物，並且該等衍生物化合物可同樣地併入用治療有效量之此衍生物化合物及醫藥上可接受之載劑或稀釋劑來製備之醫藥組成物中。 The compounds of the present invention can also be used to make derivative compounds useful as medicaments, and these derivative compounds can be similarly incorporated with a therapeutically effective amount of this derivative compound and a pharmaceutically acceptable carrier or diluent In the prepared pharmaceutical composition.
本發明之化合物，及其之此等衍生物，可有用於治療人及動物之症狀、疾病及病症。此等化合物可配製成醫藥組成物並且以適應於選定投予途徑之各種形式投予需要治療之個體，例如哺乳動物，諸如人患者。例如本發明之化合物可被配製成用於經口、經鼻、腹膜內或非經腸、藉由靜脈內、肌肉內、局部、或皮下途徑、或藉由注射至組織中來投予。 The compounds of the present invention, and these derivatives, can be useful for the treatment of symptoms, diseases and conditions in humans and animals. These compounds can be formulated into pharmaceutical compositions and administered to individuals in need of treatment, such as mammals, such as human patients, in various forms suitable for the selected route of administration. For example, the compounds of the invention can be formulated for oral, nasal, intraperitoneal or parenteral administration, by intravenous, intramuscular, topical, or subcutaneous routes, or by injection into tissues.
因此，本發明之化合物可全身投予，例如，與醫藥上可接受之媒劑諸如惰性稀釋劑或可吸收之食用載劑組合來經口投予，或藉由吸入或吹入來投予。其等可圍封於硬或軟殼明膠膠囊中、可壓縮成錠劑、或可直接併入患者膳食之食物中。對於經口治療投予，化合物可與一或多種賦形劑組合並且以可攝取錠劑、口腔錠劑、喉錠、膠囊、酏劑、懸浮液、糖漿、糯米紙囊劑及類似物之形式來使用。化合物可與惰性粉狀載劑組合並且被個體吸入或吹入。此等組成物及製劑應含有至少0.1%本發明之化合物。當然，存在於此等組成物及製劑中之本發明化合物之百分比可變化並且可方便地在給定單位劑型之約2重量%至約60重量%之間。此等治療上有用組成物中之化合物之量使得將獲得有效劑量位準。 Thus, the compounds of the present invention can be administered systemically, for example, orally in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an absorbable food carrier, or by inhalation or insufflation. They can be enclosed in hard or soft shell gelatin capsules, can be compressed into lozenges, or can be directly incorporated into the food of the patient's diet. For oral therapeutic administration, the compound can be combined with one or more excipients and in the form of ingestible tablets, buccal tablets, throat tablets, capsules, elixirs, suspensions, syrups, glutinous rice sachets and the like To use. The compound can be combined with an inert powdered carrier and inhaled or insufflated by the individual. These compositions and preparations should contain at least 0.1% of the compound of the present invention. Of course, the percentage of compounds of the invention present in such compositions and formulations can vary and can conveniently be between about 2% and about 60% by weight of a given unit dosage form. The amount of the compound in these therapeutically useful compositions is such that an effective dosage level will be obtained.
錠劑、喉錠、丸劑、膠囊及類似物亦可含有下列者：黏合劑諸如黃蓍樹膠、***樹膠、玉米澱粉或明膠；賦形劑諸如磷酸氫鈣；崩解劑諸如玉米澱粉、馬鈴薯澱粉、褐藻酸及類似物；潤滑劑諸如硬脂酸鎂；及甜味劑諸如蔗糖、果糖、乳糖、或阿斯巴甜、或可添加調味劑諸如 薄荷、冬青油、或櫻桃調味劑。當單位劑型係膠囊時，其除了含有上述類型之材料以外，還可含有液體載劑，諸如植物油或聚乙二醇。各種其他材料可以塗層形式存在或另外用於修改固體單位劑型之外觀。例如，錠劑、丸劑、或膠囊可用明膠、蠟、蟲膠、或糖及類似物塗佈。糖漿或酏劑可含有活性化合物、作為甜味劑之蔗糖或果糖、作為防腐劑之對羥基苯甲酸甲酯及對羥基苯甲酸丙酯、染料及調味劑諸如櫻桃或甜橙香精。當然，用於製備任何單位劑型之任何材料應為醫藥上可接受的並且在所使用量下實質上無毒。另外，化合物可併入持續釋放製劑及裝置中。例如，化合物可併入延時釋放膠囊、延時釋放錠劑、延時釋放丸劑、及延時釋放聚合物或奈米粒子中。 Lozenges, throat lozenges, pills, capsules and the like may also contain the following: binders such as tragacanth gum, gum arabic, corn starch or gelatin; excipients such as calcium hydrogen phosphate; disintegrants such as corn starch, potato starch , Alginic acid and the like; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavoring agents such as mint, wintergreen oil, or cherry flavorings can be added. When the unit dosage form is a capsule, it may contain a liquid carrier, such as vegetable oil or polyethylene glycol, in addition to the above-mentioned materials. Various other materials may be present as coatings or otherwise used to modify the appearance of solid unit dosage forms. For example, tablets, pills, or capsules can be coated with gelatin, wax, shellac, or sugar and the like. Syrups or elixirs may contain active compounds, sucrose or fructose as sweeteners, methyl and propyl parabens as preservatives, dyes and flavoring agents such as cherry or orange flavors. Of course, any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the compound can be incorporated into sustained-release preparations and devices. For example, the compound may be incorporated into delayed-release capsules, delayed-release tablets, delayed-release pills, and delayed-release polymers or nanoparticles.
化合物亦可藉由輸注或注射來靜脈內或腹膜內投予。化合物之溶液可在水中製備，可選地與無毒界面活性劑混合。分散液亦可在甘油、液體聚乙二醇、三乙酸甘油酯及其混合物中；以及在油中製備。在儲存及使用之固有條件下，此等製劑可含有防腐劑以防止微生物生長。 The compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of compounds can be prepared in water, optionally mixed with non-toxic surfactants. Dispersions can also be prepared in glycerin, liquid polyethylene glycol, triacetin and mixtures thereof; and in oil. Under inherent conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
適合於注射或輸注之醫藥劑型可包括無菌水溶液或分散液或包含化合物之無菌粉劑，其適應於臨時製備無菌可注射或可輸注溶液或分散液，且可選地囊封於脂質體中。在所有情況下，最終劑型應為無菌、流體，並且在製造及儲存條件下穩定。液體載劑或媒劑可為溶劑或液體分散媒質，其包含例如水、乙醇、多元醇(例如甘油、丙二醇、液體聚乙二醇及類似物)、植物油、無毒甘油酯及其合適混合物。適當流動性可例如藉由形成脂質體、在分散液的情況下藉由維持所需粒徑、或藉由使用界面活性劑來維持。預防微生物之作用可藉由各種抗細菌及抗真菌劑，例如，對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞及類似物來實現。在許多情況下，包括等滲劑例如糖、緩衝劑、或氯化鈉係較佳的。可注射組成物之延長吸收可藉由在組成物中使用延遲吸收之試劑，例如，單硬脂酸鋁及明膠來實現。 Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing compounds, which are suitable for the temporary preparation of sterile injectable or infusible solutions or dispersions, and are optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be a solvent or a liquid dispersion medium, which contains, for example, water, ethanol, polyol (eg, glycerin, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, non-toxic glycerides, and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by forming liposomes, by maintaining the desired particle size in the case of dispersions, or by using surfactants. The effect of preventing microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it is preferred to include isotonic agents such as sugars, buffers, or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using agents that delay absorption in the composition, for example, aluminum monostearate and gelatin.
無菌的可注射溶液藉由將所需量之化合物與根據需要的以上列舉之各種其他成分一起併入合適溶劑中，較佳隨後過濾滅菌來製備。 在用於製備無菌可注射溶液之無菌粉劑的情況下，較佳製備方法係真空乾燥及冷凍乾燥技術，產生活性成分加上存在於先前無菌過濾溶液之任何額外所需成分的粉劑。 Sterile injectable solutions are prepared by incorporating the compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, preferably followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying techniques to produce a powder of the active ingredient plus any additional required ingredients present in the previously sterile filtered solution.
對於局部投予，化合物可以純的形式來施用。然而，可能所欲者為將其等作為與可為固體或液體的皮膚學上可接受載劑組合的組成物或配方形式投予皮膚。 For topical administration, the compound can be administered in pure form. However, it may be desirable to administer it to the skin as a composition or formulation in combination with a dermatologically acceptable carrier that can be solid or liquid.
有用之固體載劑包括細分固體諸如滑石粉、黏土、微晶纖維素、二氧化矽、氧化鋁及類似物。其他固體載劑包括無毒聚合奈米粒子或微粒子。有用液體載劑包括水、醇、或二醇、或水/醇/二醇摻合物，於其中化合物可以可選地藉助於無毒界面活性劑以有效位準來溶解或分散。可添加佐劑諸如香料及額外抗微生物劑以優化對於給定用途之性質。所得液體組成物可從用於浸漬繃帶及其他敷料之吸收襯墊施用，或使用泵類型或氣溶膠噴霧器來噴霧至患病區域。 Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Other solid carriers include non-toxic polymeric nanoparticles or microparticles. Useful liquid carriers include water, alcohols, or glycols, or water/alcohol/diol blends, where the compounds can optionally be dissolved or dispersed at an effective level by means of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid composition can be applied from absorbent pads used to impregnate bandages and other dressings, or sprayed to the affected area using a pump type or an aerosol sprayer.
增稠劑諸如合成聚合物、脂肪酸、脂肪酸鹽及酯、脂肪醇、修飾纖維素、或修飾無機物材料亦可與液體載劑一起使用以形成可塗佈膏、凝膠、軟膏、肥皂及類似物，用於直接施用至使用者之皮膚。 Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials can also be used with liquid carriers to form coatable pastes, gels, ointments, soaps, and the like , For direct application to the user's skin.
可用於將化合物遞送至皮膚之有用皮膚組成物之實例係技術領域中已知的；例如，參見Jacquet等人(美國專利案第4,608,392號)、Geria(美國專利案第4,992,478號)、Smith等人(美國專利案第4,559,157號)、及Wortzman((美國專利案第4,820,508號)，其全部以引用形式併入本文。 Examples of useful skin compositions that can be used to deliver compounds to the skin are known in the art; for example, see Jacquet et al. (US Patent No. 4,608,392), Geria (US Patent No. 4,992,478), Smith et al. (US Patent No. 4,559,157), and Wortzman ((US Patent No. 4,820,508), all of which are incorporated herein by reference.
此等配方中之本發明之治療化合物之濃度可取決於配方之性質及意欲投予途徑而廣泛地變化。例如，液體組成物諸如乳液中之化合物之濃度可較佳為自約0.1至25重量%，或更佳自約0.5至10重量%。半固體或固體組成物諸如凝膠或粉劑中之濃度可較佳為約0.1至5重量%，或更佳約0.5至2.5重量%。 The concentration of the therapeutic compound of the present invention in these formulations can vary widely depending on the nature of the formulation and the intended route of administration. For example, the concentration of the compound in the liquid composition such as an emulsion may preferably be from about 0.1 to 25% by weight, or more preferably from about 0.5 to 10% by weight. The concentration in the semi-solid or solid composition such as gel or powder may preferably be about 0.1 to 5% by weight, or more preferably about 0.5 to 2.5% by weight.
本發明之該等劑之有效劑量及投予途徑係習知的。劑之精確量(有效劑量)會在不同個體間有變化，此係取決於例如個體之物種、 年齡、體重、及一般或臨床症狀、任何所治療病症之嚴重程度或機制、所使用特定劑或媒劑、投予之方法及排程及類似物。治療有效劑量可藉由所屬技術領域中具有通常知識者已知之習知程序依經驗判定。參見例如The Pharmacological Basis of Therapeutics,Goodman and Gilman,eds.,Macmillan Publishing Co.,New York。例如，有效劑量可最初在細胞培養物檢定中或在合適動物模型中來估計。動物模型亦可用於判定合適濃度範圍及投予途徑。然後，此資訊可用於判定投予人之有用劑量及途徑。用於將小鼠及其他動物中之有效劑量外推至人的方法在此技術領域中係已知的；例如，參見美國專利第4,938,949號，其以引用形式併入本文。治療劑量亦可從可相比擬治療劑之劑量用類推的方法來選擇。 The effective dosage and administration route of the agents of the present invention are known. The precise amount (effective dose) of the agent will vary from individual to individual, depending on, for example, the species, age, weight, and general or clinical symptoms of the individual, the severity or mechanism of any condition being treated, the specific agent or Medium, method and schedule of administration, and the like. The therapeutically effective dose can be determined empirically by conventional procedures known to those of ordinary skill in the art. See, for example, The Pharmacological Basis of Therapeutics, Goodman and Gilman, eds., Macmillan Publishing Co., New York. For example, the effective dose can be estimated initially in a cell culture assay or in a suitable animal model. Animal models can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine useful doses and routes for administration. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; for example, see US Patent No. 4,938,949, which is incorporated herein by reference. The therapeutic dose can also be selected by analogy with the dose of the comparable therapeutic agent.
特定投予模式及劑量方案由主治臨床醫師，考慮到病例之詳情(例如，個體、疾病、所涉及疾病狀態、及是否治療係預防性)來選擇。治療可涉及在數天至數月，或甚至數年週期內的化合物之每天或多天劑量。 The specific mode of administration and dosage regimen are selected by the attending clinician, taking into account the details of the case (eg, individual, disease, disease state involved, and whether the treatment is prophylactic). Treatment can involve daily or multi-day doses of the compound over a period of days to months, or even years.
然而，通常，合適劑量會在自約0.001至約100mg/kg體重/天、較佳自約0.01至約100mg/kg體重/天、更佳自約0.1至約50mg/kg體重/天範圍內、或甚至更佳在自約1至約10mg/kg體重/天範圍內。例如，合適劑量可為約1mg/kg、10mg/kg、或50mg/kg體重/天。 However, in general, a suitable dosage will range from about 0.001 to about 100 mg/kg body weight/day, preferably from about 0.01 to about 100 mg/kg body weight/day, more preferably from about 0.1 to about 50 mg/kg body weight/day, Or even more preferably in the range from about 1 to about 10 mg/kg body weight/day. For example, a suitable dose may be about 1 mg/kg, 10 mg/kg, or 50 mg/kg body weight/day.
化合物方便地以單位劑型來投予；例如，每單位劑型含有約0.05至約10000mg、約0.5至約10000mg、約5至約1000mg、或約50至約500mg活性成分。 The compounds are conveniently administered in unit dosage form; for example, each unit dosage form contains about 0.05 to about 10000 mg, about 0.5 to about 10000 mg, about 5 to about 1000 mg, or about 50 to about 500 mg of active ingredient.
可投予化合物以達成峰血漿濃度，例如，自約0.25至約200μM、約0.5至約75μM、約1至約50μM、約2至約30μM、或約5至約25μM。例示性所欲血漿濃度包括至少0.25、0.5、1、5、10、25、50、75、100或200μM。例如，血漿位準可為自約1至約100微莫耳濃度或自約10至約25微莫耳濃度。此可例如藉由靜脈內注射0.05至5%化合物溶液來達成，可選地在鹽水中，或以含有約1至約100mg化合物之大丸劑形式來經口投予。所需血液位準可藉由連續或間歇輸注來保持。 Compounds can be administered to achieve peak plasma concentrations, for example, from about 0.25 to about 200 μM, about 0.5 to about 75 μM, about 1 to about 50 μM, about 2 to about 30 μM, or about 5 to about 25 μM. Exemplary desired plasma concentrations include at least 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100, or 200 μM. For example, the plasma level may be from about 1 to about 100 micromolar or from about 10 to about 25 micromolar. This can be achieved, for example, by intravenous injection of 0.05 to 5% compound solution, optionally in saline, or by oral administration in the form of a bolus containing about 1 to about 100 mg of compound. The required blood level can be maintained by continuous or intermittent infusion.
化合物可方便地以單一劑量或以在合適間隔下投予之劃分劑量來呈現，例如，以每天一個劑量或以每天兩個、三個、四個或更多個亞劑量。亞劑量本身可進一步劃分成例如多次不連續的寬鬆間隔開投予；諸如從吹入器的多次吸入。 The compounds may conveniently be presented in a single dose or in divided doses administered at suitable intervals, for example, in one dose per day or in two, three, four or more sub-doses per day. The sub-dose itself can be further divided into, for example, multiple discrete, loosely spaced administrations; such as multiple inhalations from the insufflator.
所有文件、參考文獻、及資訊，包括但不限於在本申請案中提到、引用、或涉及之雜誌文章、專利申請案、及專利之全文以引用形式併入本文，其引用程度如同每一者個別地併入一般。 All documents, references, and information, including but not limited to magazine articles, patent applications, and patents mentioned, cited, or referred to in this application are incorporated by reference in their entirety to the same degree as each Individuals are merged into the general.
式I化合物從式XIII化合物(茛菪鹼[51-34-3])((2S)-(1R,2R,4S,5S)-9-甲基-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-7-基-3-羥基-2-苯基丙酸酯氫溴酸鹽三水合物)藉由以下方案1至12描述之步驟來合成。 The compound of formula I is derived from the compound of formula XIII (scopolamine [51-34-3]) ((2S)-(1R, 2R, 4S, 5S)-9-methyl-3-oxa-9-azatricyclo [3.3.1.02,4] Nonane-7-yl-3-hydroxy-2-phenylpropionate hydrobromide trihydrate) was synthesized by the steps described in
第一步驟在方案1中繪示：
於冰浴中，在10升四頸圓底燒瓶裡面，硼氫化鈉(172g,4558mmol)以約2小時逐份添加至式XIII化合物(333g,760mmol)於3升無水乙醇中之機械攪拌懸浮液。在此時間期間，發生氣體形成，以及攪拌懸浮液，同時加溫至環境溫度隔夜。在加熱時，於大約10℃發生突然額外氣體形成及起泡。 In an ice bath, in a 10-liter four-necked round-bottom flask, sodium borohydride (172g, 4558mmol) was added portionwise to the mechanically stirred suspension of the compound of formula XIII (333g, 760mmol) in 3 liters of absolute ethanol over about 2 hours. . During this time, gas formation occurs and the suspension is stirred while warming to ambient temperature overnight. Upon heating, sudden additional gas formation and blistering occurred at about 10°C.
然後，將乳狀懸浮液濃縮至約其原始體積的一半(即約3L至1.5L)，並且觀察到額外沉澱物，從而產出此批料。同時，異丙醇(IPA)(5318mmol,1.064L)中之5M HCl用2L工業***(Et2O)稀釋。然 後，將所獲得鹽酸(HCl)溶液逐滴添加至冰冷卻批料，同時攪拌。允許白色懸浮液機械攪拌隔夜以允許硼酸鹽之完全水解。 Then, the milky suspension was concentrated to about half of its original volume (ie about 3L to 1.5L), and additional precipitate was observed, yielding this batch. At the same time, 5M HCl in isopropyl alcohol (IPA) (5318 mmol, 1.064 L) was diluted with 2 L of industrial ether (Et 2 O). Then, the obtained hydrochloric acid (HCl) solution was added dropwise to the ice-cooled batch while stirring. The white suspension was allowed to stir mechanically overnight to allow complete hydrolysis of borate.
將反應混合物過濾並且所得固體用500mL份之Et2O沖洗兩次。將乾燥固體(其含有一些Et2O)溶解於最小量10%碳酸鉀(K2CO3)水溶液(~1.5L)中直到恰好獲得透明溶液為止。將200mL之鹽水及~50g固體NaCl添加至溶液。然後，水相充分地用氯仿/甲醇(MeOH)/[MeOH中之7N NH3](85：14：1)萃取。此程序各用1.0L份此溶劑混合物執行5次。將組合之有機萃取物乾燥(硫酸鈉(Na2SO4))、過濾、並且溶劑在減壓下移除，而給出87%產率之102.2g(659mmol)呈輕微棕褐色油之式XII化合物((1R,2R,4S,5S)-9-甲基-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-7-醇)。1HNMR(CDCl3)(圖1)顯示與式XII化合物結構一致，具有少量雜質。1HNMR(400MHz，氯仿-d)δ 4.03-4.00(m,1H),3.67(s,2H),3.20-3.18(m,2H),2.52(s,3H),2.14-2.08(m,2H),1.69-1.37(m,3H)。 The reaction mixture was filtered and the resulting solid was washed twice with 500 mL portions of Et 2 O. The dried solid (which contains some Et 2 O) was dissolved in a minimum amount of 10% aqueous potassium carbonate (K 2 CO 3 ) solution (~1.5 L) until a clear solution was just obtained. 200 mL of brine and ~50 g of solid NaCl were added to the solution. Then, the aqueous phase was sufficiently extracted with chloroform/methanol (MeOH)/[7N NH 3 in MeOH] (85:14:1). This procedure was performed 5 times with 1.0 L portions of this solvent mixture. The combined organic extracts were dried (sodium sulfate (Na 2 SO 4 )), filtered, and the solvent was removed under reduced pressure to give 102.2 g (659 mmol) of formula XII in 87% yield as a slightly tan oil Compound ((1R, 2R, 4S, 5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-7-ol). 1H NMR (CDCl 3 ) (FIG. 1) shows a structure consistent with the compound of formula XII, with a small amount of impurities. 1H NMR (400MHz, chloroform- d ) δ 4.03-4.00 (m, 1H), 3.67 (s, 2H), 3.20-3.18 (m, 2H), 2.52 (s, 3H), 2.14-2.08 (m, 2H) , 1.69-1.37 (m, 3H).
下一個步驟如方案2所示進行：
以4小時時間，向式XII化合物(102.2g,659mmol)、苯甲酸(BzOH)(97g,790mmol)及三苯基膦(PPh3)(207g,790mmol)於1000mL無水四氫呋喃(THF)中之溶液逐滴添加二異丙基偶氮二羧酸酯(DIAD)(160g,790mmol,154mL)於100mL無水THF中之溶液。在添加期間，使用丙酮/乾冰將溶液保持在-35與-25℃之間。然後將透明、無色溶液從冰浴中移除並且在室溫下攪拌隔夜。 A solution of the compound of formula XII (102.2 g, 659 mmol), benzoic acid (BzOH) (97 g, 790 mmol) and triphenylphosphine (PPh 3 ) (207 g, 790 mmol) in 1000 mL of anhydrous tetrahydrofuran (THF) over 4 hours A solution of diisopropyl azodicarboxylate (DIAD) (160 g, 790 mmol, 154 mL) in 100 mL of anhydrous THF was added dropwise. During the addition, the solution was kept between -35 and -25°C using acetone/dry ice. The clear, colorless solution was then removed from the ice bath and stirred overnight at room temperature.
取得並且分析樣本，並且該分析顯示反應完成。將反應混合物濃縮、溶解於1L乙酸乙酯(EtOAc)中、用1L飽和碳酸氫鈉(NaHCO3) 萃取、並且隨後用2M HCl水溶液(1×1L,2×0.5L)萃取。組合之酸性水性萃份用1L之EtOAc再洗滌一次。將大約400g碳酸鉀(K2CO3)逐份添加至酸性水層，同時攪拌，直到不再觀察到氣體形成為止。所得溶液之pH呈輕微鹼性並且輕微混濁及黃色。然後，水相用二氯甲烷(DCM)/MeOH 9：1(3x，各1L)溶液萃取並且將組合之有機萃份用硫酸鈉(Na2SO4)乾燥、過濾、並且濃縮以提供118.3g(447mmol)式XI化合物((1R,2R,4S,5S,7r)-9-甲基-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-7-基苯甲酸酯)，然後其藉由MS(圖2)證實以67.9%產率具有98%純度。1HNMR(400MHz，氯仿-d)δ 8.07-7.93(m,2H),7.59-7.48(m,1H),7.44-7.40(m,2H),5.39-5.30(m,1H),3.63(s,2H),3.42-3.25(m,2H),2.57(s,3H),2.10-2.04(m,2H),1.92-1.86(m,2H)。 The sample was taken and analyzed, and the analysis showed that the reaction was complete. The reaction mixture was concentrated, dissolved in 1 L of ethyl acetate (EtOAc), extracted with 1 L of saturated sodium bicarbonate (NaHCO 3 ), and then extracted with 2M aqueous HCl (1×1 L, 2×0.5 L). The combined acidic aqueous extract was washed again with 1 L of EtOAc. Approximately 400 g of potassium carbonate (K 2 CO 3 ) was added portionwise to the acidic water layer while stirring until gas formation was no longer observed. The pH of the resulting solution was slightly alkaline and slightly cloudy and yellow. Then, the aqueous phase was extracted with dichloromethane (DCM)/MeOH 9:1 (3x, 1 L each) solution and the combined organic extracts were dried over sodium sulfate (Na 2 SO 4 ), filtered, and concentrated to provide 118.3 g (447 mmol) compound of formula XI ((1R, 2R, 4S, 5S, 7r)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-7-ylbenzyl Acid ester), which was then confirmed by MS (Figure 2) to have 98% purity in 67.9% yield. 1H NMR (400MHz, chloroform- d ) δ 8.07-7.93 (m, 2H), 7.59-7.48 (m, 1H), 7.44-7.40 (m, 2H), 5.39-5.30 (m, 1H), 3.63 (s, 2H), 3.42-3.25 (m, 2H), 2.57 (s, 3H), 2.10-2.04 (m, 2H), 1.92-1.86 (m, 2H).
下一個步驟如方案3所示進行：
在氮氣氛下(並非氣流)，向式XI化合物(201.9g,779mmol)於氯仿(350mL)中之溶液，添加K2CO3(452g,3270mmol)及氯甲酸乙酯(279g,2569mmol,247mL)以形成淡黃色懸浮液，然後其在回流下攪拌隔夜。 Under a nitrogen atmosphere (not a gas flow), to a solution of the compound of formula XI (201.9 g, 779 mmol) in chloroform (350 mL), add K 2 CO 3 (452 g, 3270 mmol) and ethyl chloroformate (279 g, 2569 mmol, 247 mL) To form a light yellow suspension, which was then stirred under reflux overnight.
然後取得並且分析樣本而顯示反應達到74%轉化成產物，式X化合物(1R,2R,4S,5S,7r)-乙基7-(苯甲醯基氧基)-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-9-羧酸酯)。混合物在回流溫度下進一步攪拌又24小時。 Then a sample was taken and analyzed to show that the reaction reached 74% conversion to the product, compound of formula X (1R, 2R, 4S, 5S, 7r)-ethyl 7-(benzyloxy)-3-oxa-9- Azatricyclo[3.3.1.02,4]nonane-9-carboxylate). The mixture was further stirred at reflux temperature for another 24 hours.
然後取得並分析另一個樣本，其顯示反應達到75%轉化成產物。為了驅動反應朝向完成，將額外K2CO3(53.8g,389mmol)及氯甲酸 乙酯(85g,779mmol,74.8mL)添加至反應溶液並且混合物在回流溫度下攪拌隔夜。 Then another sample was taken and analyzed, which showed that the reaction reached 75% conversion to product. To drive the reaction towards completion, additional K 2 CO 3 (53.8 g, 389 mmol) and ethyl chloroformate (85 g, 779 mmol, 74.8 mL) were added to the reaction solution and the mixture was stirred at reflux temperature overnight.
攪拌並回流隔夜之後，取得另一個樣本，其經分析而顯示反應達到81%轉化成式X化合物。 After stirring and refluxing overnight, another sample was taken, which showed that the reaction reached 81% conversion to the compound of formula X.
然後，反應混合物用500mL之DCM稀釋並且有機層用750mL之半飽和NaHCO3水溶液、750mL之0.4 MHCl水溶液、及750mL鹽水洗滌。隨後，混合物以Na2SO4乾燥，然後過濾並在減壓下濃縮，然後提供黃色油。添加300mL庚烷並且混合物劇烈地攪拌隔夜。 Then, the reaction mixture was diluted with 500 mL of DCM and the organic layer was washed with 750 mL of half-saturated aqueous NaHCO 3 solution, 750 mL of 0.4 M HCl aqueous solution, and 750 mL of brine. Subsequently, the mixture was dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure, and then a yellow oil was provided. 300 mL heptane was added and the mixture was stirred vigorously overnight.
形成白色懸浮液，其含有大的白色團塊，將其用抹刀壓碎。將懸浮液經玻璃濾器過濾，用大約250mL庚烷及大約200mL戊烷沖洗。然後，懸浮液使用真空烘箱乾燥3小時，產出呈白色固體之式X化合物(219.6g,692mmol，89%產率)。產物之LCMS顯示大於95%之產率，並且質量及結構與所欲產物一致，如MS(圖3B)及1HNMR(圖3A)示出。1HNMR(400MHz，氯仿-d)δ 8.01-7.97(m,2H),7.61-7.53(m,1H),7.48-7.42(m,2H),5.48-5.39(m,1H),4.58(m,1H),4.48(m,1H),4.16(q,J=7.1Hz,2H),3.56-3.53(m,2H),2.34-2.21(m,2H),1.98-1.86(m,2H),1.27(t,J=7.1Hz,3H)。 A white suspension was formed, which contained large white clumps, which were crushed with a spatula. The suspension was filtered through a glass filter and rinsed with approximately 250 mL heptane and approximately 200 mL pentane. Then, the suspension was dried using a vacuum oven for 3 hours, yielding the compound of formula X as a white solid (219.6 g, 692 mmol, 89% yield). The LCMS of the product showed a yield of greater than 95%, and the quality and structure were consistent with the desired product, as shown by MS (Figure 3B) and 1H NMR (Figure 3A). 1H NMR (400MHz, chloroform- d ) δ 8.01-7.97 (m, 2H), 7.61-7.53 (m, 1H), 7.48-7.42 (m, 2H), 5.48-5.39 (m, 1H), 4.58 (m, 1H), 4.48(m, 1H), 4.16(q, J =7.1Hz, 2H), 3.56-3.53(m, 2H), 2.34-2.21(m, 2H), 1.98-1.86(m, 2H), 1.27 (t, J =7.1Hz, 3H).
下一個步驟如方案4所示進行：
在室溫下，在6L三頸燒瓶中，將硼氫化鈉(157g,4152mmol)添加至式X化合物(219.6g,692mmol)於1.5L無水乙醇中之懸浮 液。反應係放熱的，並且於大約4小時時間具有大於60℃之內部溫度，在反應期間觀察到極端氣體/泡沫形成。懸浮液在50℃下磁性攪拌隔夜。 At room temperature, in a 6 L three-necked flask, sodium borohydride (157 g, 4152 mmol) was added to a suspension of the compound of formula X (219.6 g, 692 mmol) in 1.5 L of absolute ethanol. The reaction is exothermic and has an internal temperature greater than 60°C over a period of approximately 4 hours, and extreme gas/foam formation was observed during the reaction. The suspension was magnetically stirred overnight at 50°C.
然後，取得樣本並且藉由TLC分析而顯示反應已經完成。所得產物係白色固體，在夜間使磁力攪拌器停止。混合物在減壓下濃縮並且白色固體殘餘物係在1L氯仿與3.5L半飽和水性NaHCO3溶液之間分配。隨後，將層分離並且水層用額外氯仿(2x，各1L)萃取。組合之有機層用1L鹽水洗滌、以Na2SO4乾燥、並且過濾，並在減壓下濃縮以提供大約220g呈白色固體之產物，其在0.6L庚烷中使用磁力攪拌器攪拌隔夜。 Then, a sample is taken and the reaction is completed by TLC analysis. The product obtained was a white solid, and the magnetic stirrer was stopped at night. The mixture was concentrated under reduced pressure and the white solid residue was partitioned between 1 L chloroform and 3.5 L half-saturated aqueous NaHCO 3 solution. Subsequently, the layers were separated and the aqueous layer was extracted with additional chloroform (2x, 1 L each). The combined organic layer was washed with 1 L of brine, dried over Na 2 SO 4 , and filtered, and concentrated under reduced pressure to provide about 220 g of the product as a white solid, which was stirred overnight in 0.6 L of heptane using a magnetic stirrer.
然後將混合物過濾掉，產物形成小球，將其壓碎並且將500mL庚烷添加至其中。混合物用磁力攪拌器劇烈地攪拌隔夜。 The mixture was then filtered off, the product formed into pellets, crushed and 500 mL of heptane was added to it. The mixture was vigorously stirred overnight with a magnetic stirrer.
將混合物攪拌隔夜之後，灰白色懸浮液仍然含有小球，其然後用抹刀壓碎。將懸浮液過濾並且殘餘物用大約300mL庚烷沖洗並且藉由真空乾燥，產出大約148g產物。取得樣本並且藉由1HNMR分析而顯示結構與式IX化合物(1R,2R,4S,5S,7r)-乙基7-羥基-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-9-羧酸酯)一致，(圖4)。 After stirring the mixture overnight, the off-white suspension still contained small balls, which were then crushed with a spatula. The suspension was filtered and the residue was rinsed with approximately 300 mL heptane and dried by vacuum, yielding approximately 148 g of product. A sample was taken and analyzed by 1H NMR analysis to show the structure and the compound of formula IX (1R, 2R, 4S, 5S, 7r)-ethyl 7-hydroxy-3-oxa-9-azatricyclo[3.3.1.02,4 ] Nonane-9-carboxylate), (Figure 4).
將殘餘物在大約300mL之Et2O中攪拌1小時。將白色懸浮液過濾；並且殘餘物再次用大約300mL之Et2O沖洗，然後藉由真空乾燥(在N2流下)以產生式IX化合物(122g,572mmol，82%產率)。1HNMR(400MHz，氯仿-d)δ 4.50(m,1H),4.41(m,1H),4.23-4.09(m,3H),3.42-3.39(m,2H),2.15-2.08(m,2H),1.73-1.62(m,2H),1.44(d,J=5.9Hz,1H),1.26(t,J=7.1Hz,3H)。 The residue was stirred in approximately 300 mL of Et 2 O for 1 hour. The white suspension was filtered; and the residue was washed again with approximately 300 mL of Et 2 O, and then dried by vacuum (under N 2 flow) to give the compound of formula IX (122 g, 572 mmol, 82% yield). 1H NMR (400MHz, chloroform- d ) δ 4.50 (m, 1H), 4.41 (m, 1H), 4.23-4.09 (m, 3H), 3.42-3.39 (m, 2H), 2.15-2.08 (m, 2H) , 1.73-1.62 (m, 2H), 1.44 (d, J = 5.9Hz, 1H), 1.26 (t, J = 7.1Hz, 3H).
下一個步驟如方案5所示進行：
在0℃下，將三乙基胺(22.78g,225mmol,31.4mL)及甲磺醯基-Cl(23.64g,206mmol,16.08mL)逐滴添加至式IX化合物(40g,188mmol)於DCM(500mL)中之溶液。一旦添加完成，將冰浴移除並且攪拌輕微乳狀懸浮液同時加溫至室溫。 At 0°C, triethylamine (22.78 g, 225 mmol, 31.4 mL) and mesylate-Cl (23.64 g, 206 mmol, 16.08 mL) were added dropwise to the compound of formula IX (40 g, 188 mmol) in DCM ( 500mL). Once the addition is complete, the ice bath is removed and the slightly milky suspension is stirred while warming to room temperature.
1小時之後，取得樣本並且藉由TLC分析，其顯示發生完全轉化。然後，反應混合物用500mL水洗滌兩次。DCM層看似乳狀並且以Na2SO4乾燥(其使層變得更清透)，然後過濾並在減壓下濃縮以提供稠油。油用甲苯汽提兩次以提供54.2g淺棕褐色固體，其含有21 w%甲苯。 After 1 hour, a sample was taken and analyzed by TLC, which showed that complete conversion occurred. Then, the reaction mixture was washed twice with 500 mL of water. The DCM layer looks milky and is dried over Na 2 SO 4 (which makes the layer more clear), then filtered and concentrated under reduced pressure to provide a thick oil. The oil was stripped twice with toluene to provide 54.2 g of light tan solid, which contained 21 w% toluene.
固體在真空，50℃下進一步乾燥直到重量保持恆定於43.2g(148mmol；78.9%產率)為止，產出式VIII化合物((1R,2R,4S,5S,7r)-乙基7-((甲基磺醯基)氧基)-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-9-羧酸酯)。取得樣本並且結構藉由1HNMR證實(圖5)。1HNMR(400MHz，氯仿-d)δ 5.11-5.02(m,1H),4.54-4.53(m,1H),4.44-4.43(m,1H),4.13(q,J=7.1Hz,2H),3.47-3.45(m,2H),3.00(s,3H),2.28-2.23(m,2H),2.00-1.90(m,2H),1.25(t,J=7.1Hz,3H)。 The solid was further dried under vacuum at 50°C until the weight remained constant at 43.2 g (148 mmol; 78.9% yield), yielding the compound of formula VIII ((1R, 2R, 4S, 5S, 7r)-ethyl 7-( Methanesulfonyl)oxy)-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate). A sample was taken and the structure was confirmed by 1H NMR (Figure 5). 1H NMR (400MHz, chloroform- d ) δ 5.11-5.02 (m, 1H), 4.54-4.53 (m, 1H), 4.44-4.43 (m, 1H), 4.13 (q, J = 7.1Hz, 2H), 3.47 -3.45(m, 2H), 3.00(s, 3H), 2.28-2.23(m, 2H), 2.00-1.90(m, 2H), 1.25(t, J =7.1Hz, 3H).
下一個步驟如方案6所示進行：
將氰化鉀(12.14g,186mmol)及18-冠-6(1,4,7,10,13,16-六氧雜環十八烷)(0.493g,1.864mmol)添加至式VIII化合物(19.89g,62.1mmol,91%)於300mL無水二甲亞碸中之溶液以形成淡黃色溶液，其在65℃下攪拌兩天半、或大約65小時，以產出淺棕色溶液。取得樣本並且 藉由TLC(庚烷/DME1：1，需要鉬酸鹽染色)來分析，其顯示清潔轉化成所欲產物(未觀察到外向-差向異構物副產物)，然而，反應未進行至完成，因為亦觀察到起始物質。 Potassium cyanide (12.14g, 186mmol) and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) (0.493g, 1.864mmol) were added to the compound of formula VIII ( 19.89g, 62.1mmol, 91%) in 300mL anhydrous dimethyl sulfoxide to form a pale yellow solution, which was stirred at 65°C for two and a half days, or about 65 hours, to produce a light brown solution. Samples were taken and analyzed by TLC (heptane/DME 1:1, molybdate staining required), which showed clean conversion to the desired product (exo-epimer byproducts were not observed), however, the reaction did not Proceed to completion because the starting material is also observed.
攪拌持續總共118小時，然後允許棕色溶液冷卻至室溫，並且在分配於2L之EtOAc與2L之水之間之前，與額外批料組合。該等層分層並且有機層用1L鹽水洗滌兩次、以Na2SO4乾燥、並且過濾，並在減壓下濃縮以提供粗製產物，式VII化合物((1R,2R,4S,5S,7s)-乙基7-氰基-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-9-羧酸酯)。 Stirring continued for a total of 118 hours, then the brown solution was allowed to cool to room temperature and was combined with additional batches before being partitioned between 2 L of EtOAc and 2 L of water. The layers were separated and the organic layer was washed twice with 1 L brine, dried over Na 2 SO 4 , and filtered, and concentrated under reduced pressure to provide the crude product, compound of formula VII ((1R, 2R, 4S, 5S, 7s )-Ethyl 7-cyano-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-carboxylate).
所得產物藉由重力管柱層析(750g二氧化矽，庚烷/[5至>50% EtOAc])純化以提供15.1g白色固體，或式VII化合物。取得樣本並且藉由1HNMR(圖6)分析，其證明產物與式VII結構一致，雖然產物確實含有10 w%外向-副產物(其對於後續反應係不成問題的)及7.5 w%庚烷。在對於溶劑及副產物含量進行校正之後，所有實驗之組合產率係7.55g，或45%產率。1HNMR(400MHz，氯仿-d)δ 4.53-4.52(m,1H),4.43-4.41(m,1H),4.12(q,J=7.1Hz,2H),3.70-3.68(m,2H),2.93-2.89(m,1H),2.22-2.12(m,2H),2.04-1.98(m,2H),1.24(t,J=7.1Hz,3H)。 The resulting product was purified by gravity column chromatography (750 g silica, heptane/[5 to >50% EtOAc]) to provide 15.1 g white solid, or compound of formula VII. A sample was taken and analyzed by 1H NMR (Figure 6), which proved that the product was consistent with the structure of Formula VII, although the product did contain 10 w% extro-byproduct (which is not a problem for the subsequent reaction system) and 7.5 w% heptane. After correcting for the solvent and by-product content, the combined yield for all experiments was 7.55g, or 45% yield. 1H NMR (400MHz, chloroform- d ) δ 4.53-4.52 (m, 1H), 4.43-4.41 (m, 1H), 4.12 (q, J = 7.1Hz, 2H), 3.70-3.68 (m, 2H), 2.93 -2.89(m,1H),2.22-2.12(m,2H),2.04-1.98(m,2H),1.24(t, J =7.1Hz,3H).
下一個步驟如方案7所示進行：
將雷氏鎳於水中之50%漿液添加至式VII化合物(18.20g,82mmol)於350mL之MeOH/200mL之氨(於MeOH中，7N)中之溶液。溶液保持在氮氣氛下並且在劇烈地攪拌下添加雷氏鎳漿液直到獲得暗黑色懸浮液為止。將反應容器排空並且用H2氣球再填充，重複兩次，然 後在45℃下在由氣球產生之H2氣氛中攪拌。3小時之後，取得樣本並且藉由TLC使用庚烷/二甲氧基乙烷(DME)1：1來分析，其證明反應完成。 A 50% slurry of Raney nickel in water was added to a solution of the compound of formula VII (18.20 g, 82 mmol) in 350 mL of MeOH/200 mL of ammonia (in MeOH, 7N). The solution was kept under a nitrogen atmosphere and the Rae nickel slurry was added with vigorous stirring until a dark black suspension was obtained. The reaction vessel was evacuated and refilled with H 2 balloons, repeated twice, and then stirred at 45° C. in a H 2 atmosphere generated by balloons. After 3 hours, a sample was taken and analyzed by TLC using heptane/dimethoxyethane (DME) 1:1, which proved that the reaction was complete.
將反應混合物在用MeOH預沖洗之短矽藻土墊上過濾。殘餘物亦用額外MeOH沖洗。濾液在減壓下濃縮以給出淡黃色油。此粗製產物主要由式VI.a化合物(1R,2R,4S,5S,7s)-乙基7-(胺基甲基)-3-氧雜-9-氮雜三環[3.3.1.02,4]壬烷-9-羧酸酯之開放胺及在較小程度上(所欲)環化胺式VI化合物(rac-(2R,3S,6S,7aS)-乙基3-羥基八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)的(所欲)環化胺所組成。 The reaction mixture was filtered on a short pad of diatomaceous earth pre-rinsed with MeOH. The residue was also rinsed with additional MeOH. The filtrate was concentrated under reduced pressure to give a light yellow oil. This crude product is mainly composed of the compound of formula VI.a (1R, 2R, 4S, 5S, 7s)-ethyl 7-(aminomethyl)-3-oxa-9-azatricyclo[3.3.1.02,4 ] Open amine of nonane-9-carboxylate and to a lesser extent (desirably) cyclized amine compound VI (rac-(2R,3S,6S,7aS)-ethyl 3-hydroxyoctahydro-1H -2,6-methyl-bridged pyrrolo[3,2-b]pyridine-1-carboxylate) composed of (desired) cyclic amines.
為了驅動主要內向-異構物之環化完成，將中間體溶解於500mL之無水乙醇中，其產生淡黃色溶液，然後將其攪拌並且回流隔夜。取得樣本，在減壓下濃縮，溶解於CDCl3中，並且藉由1HNMR(圖7)分析，其顯示中間且開放內向-異構物已經環化。進一步顯示大約9%之產物係開放外向-胺，並且一些溶劑保留。1HNMR(400MHz，氯仿-d)δ 4.46-4.01(m,5H),3.50-3.44(m,1H),3.16-3.11(m,1H),3.96-2.93(m,1H),2.10-1.66(m,5H),1.47(d,J=13.3Hz,1H),1.26(t,J=7.1Hz,3H)。 To drive the completion of the cyclization of the main inward-isomer, the intermediate was dissolved in 500 mL of absolute ethanol, which produced a pale yellow solution, which was then stirred and refluxed overnight. A sample was taken, concentrated under reduced pressure, dissolved in CDCl 3 , and analyzed by 1H NMR (Figure 7), which showed that the intermediate and open endogenous isomer had been cyclized. It is further shown that about 9% of the product is open-external-amine, and some solvent remains. 1H NMR (400MHz, chloroform- d ) δ 4.46-4.01 (m, 5H), 3.50-3.44 (m, 1H), 3.16-3.11 (m, 1H), 3.96-2.93 (m, 1H), 2.10-1.66 ( m,5H),1.47(d, J =13.3Hz,1H),1.26(t, J =7.1Hz,3H).
主要批料之黃色溶液係在減壓下濃縮並且殘餘物重新溶解於500mL之CHCl3中並且以Na2SO4乾燥。將溶液過濾並且濃縮以給出21.7g之呈黃色稠油之式VI化合物，其含有溶劑及用於下一個步驟中之開放外向-胺。 The yellow solution of the main batch was concentrated under reduced pressure and the residue was redissolved in 500 mL of CHCl 3 and dried over Na 2 SO 4 . The solution was filtered and concentrated to give 21.7 g of the compound of formula VI as a thick yellow oil containing the solvent and the open exo-amine used in the next step.
下一個步驟如方案8所示進行：
將苯甲醛(22.74g,214mmol,21.72mL)添加至式VI化合物(37.3g,165mmol)於1000mL二氯甲烷中之溶液。15分鐘之後，添加STAB(55.9g,264mmol)。然後懸浮液在室溫下攪拌隔夜。 Benzaldehyde (22.74 g, 214 mmol, 21.72 mL) was added to a solution of the compound of formula VI (37.3 g, 165 mmol) in 1000 mL of dichloromethane. After 15 minutes, STAB (55.9 g, 264 mmol) was added. The suspension was then stirred at room temperature overnight.
反應混合物用1L水及1L NaHCO3洗滌。有機層用Na2SO42乾燥並且濃縮至乾以提供55g之反應後產物，其隨後藉由重力管柱層析("600g,Hep/5至60% ETOAc)純化以得到：2.2g之外向-Bn2N-加合物；及35.3g之式V化合物(rac-(2R,3S,6S,7aS)-乙基3-羥基八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)，如藉由1HNMR(圖8B)及MS(圖8A)分析並證實。1HNMR(400MHz，氯仿-d)δ 7.35-7.30(m,4H),7.26-7.22(m,2H),4.41-4.02(m,5H),3.83-3.78(m,1H),3.66(d,J=13.3Hz,1H),3.30-3.26(m,1H),3.11-3.06(m,1H),2.35-2.31(m,1H),2.07-1.88(m,3H),1.77-1.65(m,2H),1.44(d,J=13.9Hz,1H),1.25(t,J=7.1Hz,3H)。 The reaction mixture was washed with 1 L of water and 1 L of NaHCO 3 . The organic layer was dried with Na 2 SO 4 2 and concentrated to dryness to provide 55 g of the post-reaction product, which was then purified by gravity column chromatography (“600 g, Hep/5 to 60% ETOAc) to obtain: 2.2 g outward- Bn2N-adduct; and 35.3g of the compound of formula V (rac-(2R,3S,6S,7aS)-ethyl 3-hydroxyoctahydro-1H-2,6-methylbridge pyrrolo[3,2-b ]Pyridine-1-carboxylate), as analyzed and confirmed by 1H NMR (Figure 8B) and MS (Figure 8A). 1H NMR (400MHz, chloroform- d ) δ 7.35-7.30 (m, 4H), 7.26 7.22(m, 2H), 4.41-4.02(m, 5H), 3.83-3.78(m, 1H), 3.66(d, J =13.3Hz, 1H), 3.30-3.26(m, 1H), 3.11-3.06( m,1H),2.35-2.31(m,1H),2.07-1.88(m,3H),1.77-1.65(m,2H),1.44(d, J =13.9Hz,1H),1.25(t, J = 7.1Hz, 3H).
下一個步驟如方案9所示進行：
將咪唑(15.19g,223mmol)及第三丁基二苯基氯矽烷(30.7g,112mmol,28.7mL)添加至式V化合物(35.3g,112mmol)於100mL無水N,N-二甲基甲醯胺中之溶液以形成淡黃色溶液，其在室溫下攪拌隔夜。 Imidazole (15.19 g, 223 mmol) and tert-butyldiphenylchlorosilane (30.7 g, 112 mmol, 28.7 mL) were added to the compound of formula V (35.3 g, 112 mmol) in 100 mL of anhydrous N,N-dimethylformamide The solution in the amine to form a pale yellow solution, which was stirred overnight at room temperature.
攪拌完成之後，取得樣本並且藉由LCMS分析，其顯示反應完成。 After the stirring was completed, a sample was taken and analyzed by LCMS, which showed that the reaction was completed.
然後，溶液在減壓下濃縮以產生油狀殘餘物，其用750mL之DCM稀釋並且用750mL之1：1飽和NaHCO3水溶液及水來洗滌。隨後 溶液用750mL鹽水洗滌。有機層以Na2SO4乾燥，過濾，並且濃縮以提供大約65g反應後產物，如藉由TLC證實。 Then, the solution was concentrated under reduced pressure to produce an oily residue, which was diluted with 750 mL of DCM and washed with 750 mL of 1:1 saturated aqueous NaHCO 3 and water. The solution was then washed with 750 mL of brine. The organic layer was dried with Na 2 SO 4 , filtered, and concentrated to provide approximately 65 g of the post-reaction product, as confirmed by TLC.
反應後產物藉由重力管柱層析(大約近似600g,Hep/5至15% EtOAc)來純化，其提供59.5g，或90%產率之呈很稠之無色油之式IV化合物(rac-(2R,3R,6S,7aS)-乙基4-苄基-3-((第三丁基二苯基矽基)氧基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)。取得樣本並且藉由1HNMR(圖9B)及LCMS(圖9A)分析，其顯示產物與式IV結構一致並且含有6 w/w%庚烷。1HNMR(400MHz，氯仿-d)δ 7.72-7.66(m,4H),7.47-7.36(m,6H),7.26-7.16(m,3H),7.12-7.09(m,2H),4.62-4.48(m,1H),4.26(s,1H),4.22-4.03(m,3H),3.40-3.29(m,2H),2.89-2.78(m,2H),1.92-1.76(m,4H),1.62-1.52(m,1H),1.31-1.23(m,3H),1.17-1.11(m,1H),1.02(s,9H)。 The product after the reaction is purified by gravity column chromatography (approximately 600g, Hep/5 to 15% EtOAc), which provides 59.5g, or 90% yield, of the compound of formula IV (rac- (2R,3R,6S,7aS)-ethyl 4-benzyl-3-((third butyldiphenylsilyl)oxy)octahydro-1H-2,6-methylbridge pyrrolo[3, 2-b] pyridine-1-carboxylate). A sample was taken and analyzed by 1H NMR (Figure 9B) and LCMS (Figure 9A), which showed that the product was consistent with Formula IV structure and contained 6 w/w% heptane. 1H NMR (400MHz, chloroform- d ) δ 7.72-7.66 (m, 4H), 7.47-7.36 (m, 6H), 7.26-7.16 (m, 3H), 7.12-7.09 (m, 2H), 4.62-4.48 ( m,1H), 4.26 (s, 1H), 4.22-4.03 (m, 3H), 3.40-3.29 (m, 2H), 2.89-2.78 (m, 2H), 1.92-1.76 (m, 4H), 1.62- 1.52 (m, 1H), 1.31-1.23 (m, 3H), 1.17-1.11 (m, 1H), 1.02 (s, 9H).
下一個步驟如方案10所示進行：
將碘三甲基矽烷(75.0g,375mmol,51ml)添加至式IV化合物(73.9g,124mmol,93%)於1.2L無水甲苯中之溶液以產生黃色反應混合物，其在85℃下攪拌隔夜。 Iodotrimethylsilane (75.0 g, 375 mmol, 51 ml) was added to a solution of the compound of formula IV (73.9 g, 124 mmol, 93%) in 1.2 L of anhydrous toluene to produce a yellow reaction mixture, which was stirred overnight at 85°C.
然後，取得樣本並且藉由TLC分析，其顯示反應已經完成。所得反應混合物係深色溶液，並且允許冷卻至室溫(懸浮液)並且用250mL之MeOH來淬滅。隨後將混合物濃縮至大約250mL。然後添加750mL之DCM並且混合物用750mL之1：1飽和NaHCO3水溶液/H2O來洗滌。然後，有機層用750mL鹽水洗滌、以Na2SO4乾燥、過濾、並且在 減壓下濃縮以提供大約72g，或92%產率之呈深黃色/橙色油之式III化合物(rac-(2R,3R,6S,7aS)-4-苄基-3-((第三丁基二苯基矽基)氧基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶)。 Then, a sample is taken and analyzed by TLC, which shows that the reaction has been completed. The resulting reaction mixture was a dark solution and was allowed to cool to room temperature (suspension) and quenched with 250 mL of MeOH. The mixture was then concentrated to approximately 250 mL. Then 750 mL of DCM was added and the mixture was washed with 750 mL of 1:1 saturated aqueous NaHCO 3 /H 2 O. Then, the organic layer was washed with 750 mL of brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to provide approximately 72 g, or 92% yield of the compound of formula III (rac-(2R ,3R,6S,7aS)-4-benzyl-3-((third butyldiphenylsilyl)oxy)octahydro-1H-2,6-methylbridge pyrrolo[3,2-b] Pyridine).
取得樣本並且藉由LCMS(圖10)分析，其顯示正確質量，並且產物具有約80%之純度，其中於0.448之峰係甲苯。1HNMR(400MHz，氯仿-d)δ 7.69-7.63(m,4H),7.47-7.37(m,6H),7.26-7.12(m,5H),4.36(s,1H),3.73-3.70(m,1H),3.39(d,J=13.7Hz,1H),3.26(d,J=7.6Hz,1H),3.06(s,1H),2.90(d,J=13.7Hz,1H),2.79-2.74(m,1H),2.41(bs,1H),1.90-1.80(m,4H),1.67-1.64(m,1H),1.11-0.99(m,10H)。 A sample was taken and analyzed by LCMS (Figure 10), which showed the correct quality, and the product had a purity of about 80%, with a peak at 0.448 of toluene. 1H NMR (400MHz, chloroform-d) δ 7.69-7.63 (m, 4H), 7.47-7.37 (m, 6H), 7.26-7.12 (m, 5H), 4.36 (s, 1H), 3.73-3.70 (m, 1H), 3.39(d, J =13.7Hz, 1H), 3.26(d, J = 7.6Hz, 1H), 3.06(s, 1H), 2.90(d, J =13.7Hz, 1H), 2.79-2.74( m, 1H), 2.41 (bs, 1H), 1.90-1.80 (m, 4H), 1.67-1.64 (m, 1H), 1.11-0.99 (m, 10H).
下一個步驟如方案11所示進行：
Et3N(48.3g,477mmol,0.067L)及二碳酸二(第三丁基)酯(Boc2O)(39.1g,179mmol)添加至式III化合物(72g,119mmol,80%)於1L二氯甲烷中之溶液以形成淡黃色溶液，其在室溫下攪拌過週末。 Et 3 N (48.3 g, 477 mmol, 0.067 L) and di(t-butyl) dicarbonate (Boc 2 O) (39.1 g, 179 mmol) were added to the compound of formula III (72 g, 119 mmol, 80%) in 1 L The solution in methyl chloride to form a pale yellow solution, which was stirred at room temperature over the weekend.
取得樣本並且藉由TLC分析，其顯示反應完成。溶液用250mL之DCM稀釋並且用1L飽和NaHCO3水溶液及1L鹽水洗滌。然後，有機層以Na2SO4乾燥、過濾、並且濃縮以提供大約80g粗製產物。藉由重力管柱層析(800g，庚烷/[EtOAcl至>10%])純化而提供68.4g，或94%產率之呈無色玻璃之式II化合物(rac-(2R,3R,6S,7aS)-第三丁基4-苄基-3-((第三丁基二苯基矽基)氧基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)。取得樣本並且藉由1HNMR(圖11A)及LCMS(圖11B)分析，其顯示產物與式II結構之間一致，並且進一步顯示產物含有4 w/w%庚烷。1HNMR(400MHz，氯仿-d)δ 7.73-7.65(m,4H),7.47-7.35(m,6H), 7.24-7.10(m,5H),4.53-4.40(m,1H),4.24(d,J=3.8Hz,1H),4.10-3.92(m,1H),3.44-3.32(m,2H),2.87(d,J=13.6Hz,1H),2.33-2.77(m,1H),1.93-1.72(m,4H),1.65-1.54(m,1H),1.50-1.47(m,9H),1.10-1.02(m,10H)。 A sample was taken and analyzed by TLC, which showed that the reaction was complete. The solution was diluted with 250 mL of DCM and washed with 1 L saturated aqueous NaHCO 3 and 1 L brine. Then, the organic layer was dried with Na 2 SO 4 , filtered, and concentrated to provide about 80 g of crude product. Purification by gravity column chromatography (800 g, heptane/[EtOAc1 to >10%]) provided 68.4 g, or 94% yield, of the compound of formula II (rac-(2R,3R,6S, 7aS)-tert-butyl 4-benzyl-3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6-methylbridge pyrrolo[3,2-b]pyridine -1-carboxylate). A sample was taken and analyzed by 1H NMR (Figure 11A) and LCMS (Figure 11B), which showed that the product was consistent with the structure of Formula II, and further showed that the product contained 4 w/w% heptane. 1H NMR (400MHz, chloroform- d ) δ 7.73-7.65 (m, 4H), 7.47-7.35 (m, 6H), 7.24-7.10 (m, 5H), 4.53-4.40 (m, 1H), 4.24 (d, J =3.8Hz,1H), 4.10-3.92(m,1H),3.44-3.32(m,2H),2.87(d, J =13.6Hz,1H),2.33-2.77(m,1H),1.93-1.72 (m,4H),1.65-1.54(m,1H),1.50-1.47(m,9H),1.10-1.02(m,10H).
下一個步驟如方案12所示進行：
在氮流下，10%活性碳(7g,125mmol)載鈀添加至式II化合物(72.9g,125mmol)於600mL乙酸中之溶液。將容器關上並且所得混合物在50℃且由氣球產生氫氣氛下攪拌2小時。 Under nitrogen flow, palladium on 10% activated carbon (7 g, 125 mmol) was added to a solution of the compound of formula II (72.9 g, 125 mmol) in 600 mL of acetic acid. The container was closed and the resulting mixture was stirred at 50°C for 2 hours under a hydrogen atmosphere generated by a balloon.
將混合物在50℃下攪拌隔夜。黑色懸浮液以經EtOH沖洗之矽藻土過濾並且濾液在減壓下濃縮。殘餘物用0.5L甲苯汽提兩次，然後其溶解於1L***中。有機層用1L之10%(w/v)K2CO3水溶液、1L鹽水洗滌、以Na2SO4乾燥、過濾、並且在減壓下濃縮，然後再次用戊烷汽提以提供58.5g稠棕褐色糖漿，式I化合物(rac-(2R,3S,6S,7aS)-第三丁基3-((第三丁基二苯基矽基)氧基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)。取得樣本並且藉由1HNMR(圖12B)及LCMS(圖12A)分析，其顯示產物與式I結構一致並且含有5.1重量%之甲苯及1.3重量%之n-戊烷。1HNMR(400MHz，氯仿-d)δ 7.68-7.63(m,4H),7.45-7.35(m,6H),4.40-4.25(m,1H),4.13-3.93(m,2H),3.41-3.36(m,1H),2.97-2.92(m,1H),2.62(d,J=11.5Hz,1H),1.96-1.78(m,2H),1.67(s,1H),1.64-1.56(m,1H),1.49-1.47(m,9H),1.16-1.13(m,1H),1.05-1.04(m,9H)。 The mixture was stirred at 50°C overnight. The black suspension was filtered through diatomaceous earth rinsed with EtOH and the filtrate was concentrated under reduced pressure. The residue was stripped twice with 0.5 L of toluene, and then it was dissolved in 1 L of ether. The organic layer was washed with 1 L of 10% (w/v) K 2 CO 3 aqueous solution, 1 L brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure, and then stripped with pentane again to provide 58.5 g thick Tan syrup, compound of formula I (rac-(2R,3S,6S,7aS)-tert-butyl 3-((tert-butyldiphenylsilyl)oxy)octahydro-1H-2,6- (Methyl bridge pyrrolo[3,2-b]pyridine-1-carboxylate). A sample was taken and analyzed by 1H NMR (Figure 12B) and LCMS (Figure 12A), which showed that the product was structurally consistent with Formula I and contained 5.1 wt% toluene and 1.3 wt% n -pentane. 1H NMR (400MHz, chloroform- d ) δ 7.68-7.63 (m, 4H), 7.45-7.35 (m, 6H), 4.40-4.25 (m, 1H), 4.13-3.93 (m, 2H), 3.41-3.36 ( m,1H),2.97-2.92(m,1H),2.62(d, J =11.5Hz,1H),1.96-1.78(m,2H),1.67(s,1H),1.64-1.56(m,1H) , 1.49-1.47 (m, 9H), 1.16-1.13 (m, 1H), 1.05-1.04 (m, 9H).
經由具有90/10 scCO2/iPrOH+0.2%異丙胺沖提液之Welkho-1管柱上之超臨界液體層析(SFC)，將式I化合物分離成其相應鏡像異構物，如方案13所示：
將起始反應物轉換成式I化合物之此等合成步驟之概述提供於方案14中：
以下描述從式I.a化合物合成式XVIII化合物之步驟。 The steps for synthesizing the compound of formula XVIII from the compound of formula I.a are described below.
如在以下方案15中說明，首先式XIV化合物((2R*,3R*,3aS*,6S*,7aS*)-第三丁基3-((第三丁基二苯基矽基)氧基)-4-(5-氟吡啶甲醯基) 八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)係從式I.a化合物合成。 As illustrated in
11.58g(30.4mmol)之六氟磷酸1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化物(HATU)添加至5-氟吡啶甲酸(4.30g,30.4mmol)及二異丙基乙胺(DIPEA)(3.93g,30.4mmol,5.32mL)於125mL之DCM中之溶液。然後將反應混合物於室溫攪拌2小時。添加式I.a化合物(12.5g,25.4mmol)於125mL之DCM中之溶液，並且反應混合物在室溫下攪拌隔夜。 11.58g (30.4mmol) of hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide (HATU) was added to a solution of 5-fluoropicolinic acid (4.30 g, 30.4 mmol) and diisopropylethylamine (DIPEA) (3.93 g, 30.4 mmol, 5.32 mL) in 125 mL of DCM. The reaction mixture was then stirred at room temperature for 2 hours. A solution of the compound of formula I.a (12.5 g, 25.4 mmol) in 125 mL of DCM was added, and the reaction mixture was stirred at room temperature overnight.
反應混合物用200mL之DCM稀釋，用飽和NaHCO3水溶液(300mL)、1M KHSO4(300mL)及鹽水(400mL)洗滌。有機層用硫酸鈉乾燥並且濃縮以產出22.0g，(141%)式XIV化合物，如藉由LCMS(圖13)證實。 The reaction mixture was diluted with 200 mL of DCM and washed with saturated aqueous NaHCO 3 (300 mL), 1M KHSO 4 (300 mL) and brine (400 mL). The organic layer was dried with sodium sulfate and concentrated to yield 22.0 g, (141%) of the compound of formula XIV, as confirmed by LCMS (Figure 13).
如在以下方案16中說明，式XV化合物((2R*,3R*,3aS*,6S*,7aS*)-第三丁基4-(5-氟吡啶甲醯基)-3-羥基八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)然後從式XIV化合物合成。 As illustrated in
向式XIV化合物(15.64g,25.4mmol)於100mL無水四氫呋喃中之溶液添加76mL(76mmol)四丁基氟化銨(TBAF)並且反應混合物在50℃下攪拌隔夜。將反應混合物濃縮至乾並且藉由重力管柱層析(500mL二氧化矽，DCM至5% MeOH/DCM)純化以產出11.4g所欲材料，其被副產物污染。殘餘物溶解於0.25L之EtOAc中並且用0.5L鹽水洗滌兩次以產出9.50g(99%)式XV化合物，其被未識別的雜質污染，如藉由LCMS分析(圖14)指示。在接下來的反應中使用此材料。 To a solution of the compound of formula XIV (15.64 g, 25.4 mmol) in 100 mL of anhydrous tetrahydrofuran was added 76 mL (76 mmol) of tetrabutylammonium fluoride (TBAF) and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated to dryness and purified by gravity column chromatography (500 mL silica, DCM to 5% MeOH/DCM) to yield 11.4 g of the desired material, which was contaminated with by-products. The residue was dissolved in 0.25 L of EtOAc and washed twice with 0.5 L of brine to yield 9.50 g (99%) of the compound of formula XV, which was contaminated with unidentified impurities, as indicated by LCMS analysis (Figure 14). This material is used in the next reaction.
如在以下方案17中說明，式XVI化合物((2R*,3R*,3aS*,6S*,7aS*)-第三丁基3-((環丙烷羰基)氧基)-4-(5-氟吡啶甲醯基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)然後從式XV化合物合成。 As illustrated in
式XV化合物(3.5g,9.27mmol)溶解於40mL吡啶中，隨後添加1.133g(9.27mmol)之4-二甲基胺基吡啶(DMAP)及20.16mL(23.18mmol)環丙烷甲醯氯。將反應混合物在60℃下攪拌3小時。然後，反應混合物用250mL乙酸乙酯稀釋並且用KHSO4(0.5M,200mL)、NaHCO3(飽和水溶液，200mL)及鹽水(200mL)洗滌。有機相用硫酸鈉乾燥、過濾、並且將溶劑蒸發。粗製殘餘物藉由重力管柱層析(二氧化矽，50% EtOAc/庚烷至100% EtOAc)純化以產出3.40g(82%)式XVI化合物，如藉由LCMS(圖15)證實。 The compound of formula XV (3.5 g, 9.27 mmol) was dissolved in 40 mL of pyridine, followed by the addition of 1.133 g (9.27 mmol) of 4-dimethylaminopyridine (DMAP) and 20.16 mL (23.18 mmol) of cyclopropanecarboxamide. The reaction mixture was stirred at 60°C for 3 hours. Then, the reaction mixture was diluted with 250 mL of ethyl acetate and washed with KHSO 4 (0.5M, 200 mL), NaHCO 3 (saturated aqueous solution, 200 mL), and brine (200 mL). The organic phase was dried with sodium sulfate, filtered, and the solvent was evaporated. The crude residue was purified by gravity column chromatography (silica, 50% EtOAc/heptane to 100% EtOAc) to yield 3.40 g (82%) of the compound of formula XVI, as confirmed by LCMS (Figure 15).
如在以下方案18中說明，式XVII化合物((2R*,3R*,3aS*,6S*,7aS*)-4-(5-氟吡啶甲醯基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-3-基環丙烷羧酸酯)然後從式XVI化合物合成。 As illustrated in Scheme 18 below, the compound of formula XVII ((2R*, 3R*, 3aS*, 6S*, 7aS*)-4-(5-fluoropyridinecarboxamide)octahydro-1H-2,6-methyl Bridged pyrrolo[3,2-b]pyridin-3-ylcyclopropane carboxylate) is then synthesized from the compound of formula XVI.
在250mL圓底燒瓶中，3.40g(7.63mmol)式XVI化合物溶解於30mL之DCM中。添加三氟乙酸(46.1g,404mmol,30ml)並且反應混合物在室溫下攪拌90分鐘。反應混合物蒸發至乾並且與甲苯一起共蒸發兩次。此殘餘物在150mL之CHCl3與150mL之飽和Na2CO3(aq)之間分配，並且將有機相分離。水層用100mL之CHCl3萃取兩次。組合之有機層用100mL鹽水洗滌、以Na2SO4乾燥、過濾、蒸發至乾並、且與DCM一起共蒸發一次以產出2.791g(106%)式XVII化合物，如藉由LCMS分析(圖16)證實。 In a 250 mL round bottom flask, 3.40 g (7.63 mmol) of the compound of formula XVI was dissolved in 30 mL of DCM. Trifluoroacetic acid (46.1 g, 404 mmol, 30 ml) was added and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was evaporated to dryness and co-evaporated twice with toluene. This residue was partitioned between 150 mL of CHCl 3 and 150 mL of saturated Na 2 CO 3 (aq), and the organic phase was separated. The aqueous layer was extracted twice with 100 mL of CHCl 3 . The combined organic layer was washed with 100 mL of brine, dried over Na 2 SO 4 , filtered, evaporated to dryness, and co-evaporated once with DCM to yield 2.791 g (106%) of the compound of formula XVII, as analyzed by LCMS (Fig. 16) Confirm.
如在以下方案19中說明，式XVIII化合物從式XVII化合物合成。 As illustrated in
式XVII化合物溶解於2mL之DCM中，隨後添加胡椒醛(1.3eq：36.17mg；0.24mmol)。在室溫下攪拌2小時之後，添加64.80mg(0.31mmol)STAB。反應混合物在室溫下攪拌隔夜、蒸發至乾、並且藉由製備HPLC純化以產出68.4mg(77%)式XVIII化合物，如藉由LCMS(圖17A)及1HNMR(圖17B)證實。 The compound of formula XVII was dissolved in 2 mL of DCM, and then piperonal (1.3 eq: 36.17 mg; 0.24 mmol) was added. After stirring at room temperature for 2 hours, 64.80 mg (0.31 mmol) of STAB was added. The reaction mixture was stirred at room temperature overnight, evaporated to dryness, and purified by preparative HPLC to yield 68.4 mg (77%) of the compound of formula XVIII, as confirmed by LCMS (Figure 17A) and 1H NMR (Figure 17B).
以下描述從式I.b化合物合成式XXII化合物之步驟。 The procedure for synthesizing the compound of formula XXII from the compound of formula I.b is described below.
如在以下方案20中說明，首先式XIX化合物((2S*,3S*,6R*,7aR*)-第三丁基3-((第三丁基二苯基矽基)氧基)-4-(2-甲氧基乙醯基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)從式I.b化合物合成。 As illustrated in
3.17g(35.2mmol,2.70mL)之2-甲氧基乙酸溶解於124mL之DCM及4.55g(35.2mmol,6.14mL)之DIPEA中。然後添加13.40g(35.2mmol)之HATU並且混合物在環境溫度下攪拌2小時。添加12.4g(25.2mmol)之式I.b化合物於125mL之DCM中之溶液並且在環境溫度下攪拌隔夜。 3.17 g (35.2 mmol, 2.70 mL) of 2-methoxyacetic acid was dissolved in 124 mL of DCM and 4.55 g (35.2 mmol, 6.14 mL) of DIPEA. Then 13.40 g (35.2 mmol) of HATU was added and the mixture was stirred at ambient temperature for 2 hours. A solution of 12.4 g (25.2 mmol) of the compound of formula I.b in 125 mL of DCM was added and stirred at ambient temperature overnight.
反應混合物用飽和NaHCO3(200mL)水溶液、1M KHSO4(200mL)水溶液、水(200mL)及鹽水(200mL)洗滌，有機相用Na2SO4乾燥、過濾、並且將溶劑蒸發以產出23.40g粗產物，式XIX化合物。HPLC/MS分析(圖18)指示所欲材料被殘留DIPEA污染。 The reaction mixture was washed with saturated aqueous NaHCO 3 (200 mL), 1M aqueous KHSO 4 (200 mL), water (200 mL) and brine (200 mL), the organic phase was dried with Na 2 SO 4 , filtered, and the solvent was evaporated to yield 23.40 g Crude product, compound of formula XIX. HPLC/MS analysis (Figure 18) indicated that the desired material was contaminated with residual DIPEA.
如在以下方案21中說明，式XX化合物((2S*,3S*,3aS*,6R*,7aR*)-第三丁基3-羥基-4-(2-甲氧基乙醯基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-羧酸酯)然後從式XIX化合物合成。 As illustrated in
在環境溫度下，向式XIX化合物(14.23g,25.2mmol)於100mL無水四氫呋喃(THF)中之溶液，將四丁基氟化銨(TBAF)於THF(76mmol,76mL)中之1.0M溶液添加至溶液。然後反應混合物加熱至50℃並且攪拌隔夜。將粗製反應混合物濃縮至乾，並且用乙酸乙酯/庚烷之1：1溶液汽提兩次以產生23.40g粗製物質。藉由庚烷中50~100%乙酸乙酯之重力管柱層析純化，出生8.21g(定量)式XX化合物，如藉由LCMS分析(圖19)證實。 To a solution of a compound of formula XIX (14.23 g, 25.2 mmol) in 100 mL of anhydrous tetrahydrofuran (THF) at ambient temperature, add a 1.0 M solution of tetrabutylammonium fluoride (TBAF) in THF (76 mmol, 76 mL) To solution. The reaction mixture was then heated to 50°C and stirred overnight. The crude reaction mixture was concentrated to dryness and stripped twice with a 1:1 solution of ethyl acetate/heptane to produce 23.40 g of crude material. Purified by gravity column chromatography of 50-100% ethyl acetate in heptane, 8.21 g (quantitative) of the compound of formula XX was born, as confirmed by LCMS analysis (Figure 19).
如在以下方案22中說明，式XXI化合物(1-((2S*,3S*,3aS*,6R*,7aR*)-3-羥基六氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-4(2H)-基)-2-甲氧基乙酮)然後從式XX化合物合成。 As illustrated in
向式XX化合物(1.89g,5.79mmol)於35mL之DCM中之溶液添加51.8g(454mmol,35mL)三氟乙酸(TFA)並且反應混合物在室溫下攪拌1.5小時。反應混合物在減壓下蒸發至乾並且與甲苯一起共蒸發兩次。所得黏性油溶解於35mL之氯仿中並且用飽和Na2CO3水溶液洗滌。嘗試單離在有機相中之所欲材料不成功。然後水相在減壓下蒸發至乾。 To a solution of the compound of formula XX (1.89 g, 5.79 mmol) in 35 mL of DCM was added 51.8 g (454 mmol, 35 mL) trifluoroacetic acid (TFA) and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness under reduced pressure and co-evaporated twice with toluene. The resulting viscous oil was dissolved in 35 mL of chloroform and washed with saturated aqueous Na 2 CO 3 solution. Attempts to isolate only the desired materials in the organic phase were unsuccessful. The aqueous phase was then evaporated to dryness under reduced pressure.
向固體添加氯仿/MeOH之9：1混合物並且懸浮液在室溫下攪拌隔夜。過濾之後，濾液在減壓下蒸發至乾。所得固體溶解於氯仿中、過濾(使用40微米LCMS過濾器)並且在減壓下蒸發至乾以提供0.91g，或69.5%產率之呈白色發泡體之式XXI化合物，藉由LCMS(圖20)證實。然後在接下來的反應中使用如是產物。 A 9:1 mixture of chloroform/MeOH was added to the solid and the suspension was stirred at room temperature overnight. After filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting solid was dissolved in chloroform, filtered (using a 40 micron LCMS filter) and evaporated to dryness under reduced pressure to provide 0.91 g, or 69.5% yield of the compound of formula XXI as a white foam, by LCMS (Fig. 20) Confirm. Then use the same product in the next reaction.
如方案23示出，式XXII化合物(3-(((2S*,3S*,6R*,7aR*)-3-羥基-4-(2-甲氧基乙醯基)八氫-1H-2,6-甲橋吡咯并[3,2-b]吡啶-1-基)甲基)苯甲醯胺)從式XXI化合物合成。 As shown in
向式XXI化合物(193mg；0.85mmol)於2mL之DCM中之溶液添加165.4mg(1.11mmol)之3-甲醯基苯甲醯胺並且反應混合物攪拌隔夜。隨後，向反應混合物添加298.3mg(1.141mmol)三乙醯氧基硼氫化鈉並且反應混合物在室溫下攪拌隔夜。使用Genevac將反應混合物在減壓下蒸發至乾。藉由prep LCMS純化，隨後在減壓下蒸發溶劑(Genevac)而提供244mg，79.6%產率之所欲產物，式XXII化合物，如藉由LCMS(圖21A)及1HNMR(圖21B)證實。 To a solution of the compound of formula XXI (193 mg; 0.85 mmol) in 2 mL of DCM was added 165.4 mg (1.11 mmol) of 3-methylacetobenzamide and the reaction mixture was stirred overnight. Subsequently, 298.3 mg (1.141 mmol) of sodium triethoxyborohydride was added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness under reduced pressure using Genevac. Purification by prep LCMS, followed by evaporation of the solvent under reduced pressure (Genevac) provided 244 mg, 79.6% yield of the desired product, compound of formula XXII, as confirmed by LCMS (Figure 21A) and 1H NMR (Figure 21B).
足底內注射1% β-角叉菜膠可用於誘導測試個體小鼠之腳爪之局部炎症。通常，局部炎症表現為腳爪腫脹及對熱刺激敏感性增加。因此，可評鑑測試項目對於熱過敏性改變之效果。使用所闡明協定，評估式XVIII及XXII化合物之治療效果。 Intraplantar injection of 1% β-carrageenan can be used to induce local inflammation in the paws of the test individual mice. Usually, local inflammation manifests as paw swelling and increased sensitivity to thermal stimuli. Therefore, the effect of the test item on the change of heat allergy can be evaluated. Using the clarified protocol, the therapeutic effects of compounds of formula XVIII and XXII are evaluated.
在零時向動物ip投藥10mg/kg之測試化合物(對照僅給予媒劑)(測試項目溶解於20% λ-羥基丙基環糊精溶液中)。30分鐘之後，動物用異氟烷輕微麻醉，並且將蒸餾水中之0.1ml之1% λ-角叉菜膠懸浮液注射至小鼠之右後腳爪之足底側。λ-角叉菜膠投予之後3.5小時之後，將動物放置在保持於57℃下之熱板設備上，並且記錄直到第一次回應之時間。 The animals were dosed with 10 mg/kg of test compound ip at time zero (the control was given only vehicle) (the test item was dissolved in 20% λ-hydroxypropyl cyclodextrin solution). After 30 minutes, the animals were lightly anesthetized with isoflurane, and 0.1 ml of 1% λ-carrageenan suspension in distilled water was injected into the plantar side of the right hind paw of the mice. 3.5 hours after lambda-carrageenan administration, the animals were placed on a hot plate device maintained at 57°C, and the time until the first response was recorded.
當式XVIII化合物及式XXII化合物如上所述測試(n=5只動物)時，超過處理前基線回應時間之平均回應時間，如下所示。 When the compound of formula XVIII and the compound of formula XXII are tested as described above (n=5 animals), the average response time that exceeds the baseline response time before treatment is shown below.
相比之下，媒劑處理動物展示與治療前相比減少之回應時間。 In contrast, vehicle-treated animals showed reduced response time compared to before treatment.
本說明書中說明並論述之實施例僅意欲教示所屬技術領域中具有通常知識者發明人所知製造及使用本發明之最佳方式。在本說明書中沒有任何一者應被認為限制本發明之範疇。所有呈現之實例係具代表性並且是非限制性的。本發明之上述實施例可經修改或變化，而不脫離本發明，如所屬技術領域中具有通常知識者鑒於以上教示認知者。因此應瞭解，在申請專利範圍及其均等物之範疇內，本發明可用不同於所具體描述者之其他方式來實施。 The embodiments described and discussed in this specification are only intended to teach the best way to make and use the invention known to those of ordinary skill in the art. None of this description should be considered as limiting the scope of the invention. All examples presented are representative and non-limiting. The above-mentioned embodiments of the present invention may be modified or changed without departing from the present invention, as those with ordinary knowledge in the technical field in view of the above teaching and recognition. Therefore, it should be understood that within the scope of the patent application and its equivalents, the present invention can be implemented in other ways than those specifically described.
應瞭解雖然為了簡單起見，式II至XXIII化合物可能以特定掌性繪製，但是所屬技術領域中具有通常知識者將認知到如何產生並分 離此等各種異構物。因此，可瞭解式II至XXIII化合物之所有異構物係在本申請案之申請範圍內。 It should be understood that although compounds of formulae II to XXIII may be drawn with specific palms for simplicity, those with ordinary knowledge in the art will recognize how to generate and separate these various isomers. Therefore, it can be understood that all isomers of the compounds of the formulae II to XXIII are within the scope of the present application.
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| TWI686393B (en) | Therapeutic compound for pain and synthesis thereof | |
| US20240132470A1 (en) | Antibacterial Compounds |